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Old 14-06-2014, 01:53 PM   #601
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Various media outlets recently reported that a 47 year old man in the UK with only weeks to live, made a full recovery from his terminal Non-Hodgkin’s Lymphoma cancer following treatment with a recently approved drug called Brentuximab vedotin (Adcetris). His body, as seen in the scan, was riddled with approximately 70 fatal tumours. These tumours had spread to distant sites throughout his body, yet within a space of two weeks all these tumours had disappeared. The drug responsible for this remarkable recovery is part of a new class of immunotherapeutics called Antibody Drug Conjugates (ADCs). Although the therapy itself wasn’t a particularly pleasant experience (apparently the patient didn’t feel well for the first few days), it gave the patient a choice; death within a couple of weeks or a chance to be in complete remission. ADCs are also being developed for cancer of the lung, colon, prostate, brain and other solid tumours as well as leukaemia. Approximately 40 ADCs are currently undergoing clinical trials (see the enclosed list below with details and links to clinical trials).

Before (left) and after (right) treatment scans. The image on the left
shows the extent of metastatic disease (spread of cancer) in the
patient (70 tumours from Non-Hodgkin's Lymphoma). The scan on
the right demonstrates complete elimination of tumours two weeks
after treatment (the black blobs in the scan on the right are normal
(these are the brain, kidneys, and the bladder).

In this article I will discuss the following:
What is Brentuximab vedotin (Adcetris)?
What are Antibody Drug Conjugates (ADC)?
Different technologies and compounds that make up an ADC
The biotech and pharmaceutical companies that are developing ADCs for other cancers
List and links to current clinical trials investigating ADCs for other cancers
What is Brentuximab vedotin (Adcetris)?
Brentuximab vedotin or its marketing / brand name, Adcetris is a cancer treatment for lymphoma (both, Hodgkin’s and Non-Hodgekin’s Lymphoma types).
This cancer therapy is a completely new class of drug that has been in development since the early part of the 21st century and is called Antibody Drug Conjugate (ADC), although some of the components that make up this targeted cancer drug have been around for a bit longer.
Essentially ADCs are made up of 3 parts:

1. A monoclonal antibody that specifically targets cancer cells
2. A highly toxic compound (e.g. monomethyl auristatin E (MMAE))
3. Technology that links the above two entities

It is the combination that makes up this new class of novel compounds, such as Brentuximab vedotin; compounds that have added a second dimension to the monoclonal antibody treatment paradigm. Arming exquisitely specific monoclonal antibodies with a toxic payload is a truly innovative- and quite possibly effective way of treating cancer as the tumour cells get hit with a “double whammy”. In the case of Brentuximab vedotin this means that the monoclonal antibody component will target a receptor (called CD30) that is important to the tumour cell, while subsequently (once the antibody has been delivered to the interior of the cell), the antibody will release its toxic payload (a cytotoxic, microtubule-disrupting agent, called monomethyl auristatin E (MMAE)) that will then literally cause the cancer cell to self-destruct. Thankfully, ADCs are gaining acceptance in the oncology community and are expected to become a major contributor to improved cancer therapy.

What are Antibody Drug Conjugates (ADCs); a more scientific explanation

Antibody Drug Conjugates (ADCs) consist of a monoclonal Antibody (mAb) or antibody fragment which is chemically coupled (i.e. conjugated) to a cytotoxic drug via a synthetic linker (e.g. disulfide or non-cleavable thioether linker chemistry). In general, ADCs deliver deactivated cytotoxins specifically to cancer cells. Once in the tumour cell, the cytotoxins are released from the ADC, regaining their full cytotoxic activity, which in turn leads to rapid cell death. The concept and mechanistic aspects of ADCs are easy to understand and relatively straightforward, however, the design and synthesis of a fully functional and effective ADC entity is remarkably challenging. As such, several aspects of ADC design need careful consideration in order to optimise stability in circulation and the targeted local or intracellular effect.

Various schematic representations of an Antibody Drug Conjugate (ADC).
Note the difference in size; IgG antibody is approximately 150 kDa in size,
while the attached drug is around 100 times smaller. Attaching drugs to
an antibody can cause a conformational change that may inhibit function.

Considerations include isotype selection during the antibody engineering phase. Depending on the choice of IgG isotype, different mechanisms of effector action will be elicited in vivo. While, IgG1 and IgG3 are highly active in initiating Antibody Dependent Cell-Mediated Cytotoxicity (ADCC), and Complement Dependent Cytotoxicity (CDC), IgG2 and IgG4 are much less capable in evoking such an immune response. Interestingly, most ADCs currently in development are of the IgG1 isotype. Only a small number of IgG2 and IgG4 isotypes are utilised in ADC development, while IgG3 is not used used at all (probably for reasons of instability). Although, some of these isotypes belong to the IgG2 or IgG4 class, they are likely to have been modified in the hinge region in order to exert greater control in vivo, e.g. over mAb half-body formation.

In addition, linker technology and type of conjugated toxin (e.g. duocarmycin derivatives, doxorubicin, maytansine, etc…) play an important role in how (or even if) cancer cells will be killed. For example, duocarmycins disrupt the DNA of tumour cells at any phase of the cell cycle, unlike many other toxins that are conjugated to ADCs which only attack tumour cells in a dividing state. Another characteristic to take into consideration is the level of efficacy in treating tumour cells that are multi-drug resistant (again, pre-clinical tests have shown that duocarmycins are able to overcome resistance).
How do monoclonal antibody properties govern ADC function?
Compared to conventional cancer treatments or drugs, monoclonal antibodies (mAbs) used as pharmacological entities have physical characteristics and modes of action that are particular to this class of therapeutics. mAbs are highly specific (targeting very precisely). Dependent on the backbone design, they can induce powerful immune responses all by themselves. However, appropriate selection of antigen targets for antibody cancer therapy requires a comprehensive understanding and analysis of tumour-associated antigen expression. Unfortunately, truly tumour specific antigens have not been identified. As such, mAbs used as a cancer therapy are often targeted against tumour-associated antigens rather than antigens unique to just tumour tissue. This means that tumour associated antigens are often highly expressed on cancer cells while only a limited expression occurs within normal tissues, or that they are expressed at early stages of development (i.e. in the foetus) but not in adults (i.e. temporal difference in expression). Monoclonal antibodies used in cancer therapy are derived from various starting materials. Fully human antibodies are predominantly generated either with the use of transgenic mice and subsequent conventional hybridoma technology, or from single-chain variable fragment phage display display techniques combined with a prefabricated human constant region. Humanized antibodies are made by replacing the Complementarity-Determining Regions (CDRs) of a human IgG antibody with the CDRs of a mouse antigen-specific monoclonal antibody. In order to minimise loss of target affinity, one or more amino acid residues from the Framework Regions (FRs) are also often incorporated. Chimeric antibodies are created by joining the antigen binding variable heavy- and light-chain domains (VL and VH) of a mouse monoclonal antibody specific for a particular antigen with the constant region domains (CH1, CH2, and CH3) of a human monoclonal antibody.Please note that I will discuss these types of antibodies in more detail in a video in the near future, if you want to be notified on the day when the video is being released.

A schematic overview of the various types of monoclonal antibodies used
in cancer therapy.

Other aspects that require a sound understanding when designing mAbs are level of homogeneity of target antigen expression within tumour tissues as well as its physiological role in tumour development. Also, in contrast to mAb therapies (mAbs without being conjugated to a drug) in which a very slow internalisation process of the antigen-mAb complex is preferred in order to elicit ADCC or CDC immune responses, rapid internalisation is desirable for ADCs delivering toxins into the cancer cell and for antibodies whose action is primarily based on downregulation of cell surface receptors. Hence, target antigen and antibody isotype selection are both important factors to consider in the design of an ADC.

In summary, the safest and most efficacious mAbs used in ADC development are those that target antigens which are expressed selectively and homogeneously at a high density on the surface of malignant cells, given that intracellular concentrations of cytotoxic compounds inside cancer cells (i.e. killing of cells) is directly related to the level of antigen expression and the efficiency by which the ADCs are internalised.

Linker technology and toxins used in ADC synthesis

Attaching a drug to an antibody requires a linker that is stable in circulation in order to match the long half-life of an antibody in serum, while it should simultaneously be able to release the active form of the drug following antigen mediated internalisation by a tumour cell. Linker chemistry can be categorised on the basis of their inherent drug release mechanism. Cleavable linkers, the most common category in clinical development, release the active form of a drug as a result of either acidic and reducing conditions or enzymatic cleavage of the labile bond, while the non-cleavable linkers release the drug once the antibody is degraded in the lysosome following internalisation. For example, hydrazone bonds release the conjugated drug in the lysosome as a result of acidic conditions, whereas disulfide bonds release the attached toxic payload following intracellular reduction. The use of amide / peptide bonds has improved serum stability of ADCs considerably, while it permits rapid enzymatic cleavage once an ADC has been internalised by a cancer cell. An interesting example is the valine-citruline (peptide) based linker, which shows a substantially improved stability profile in serum (> 9 days) when compared with hydrazone-doxorubicin (43 hours). Please see different linkers in the figure

Drugs used to create ADCs

A range of tumouricidal drugs are used to create ADCs. Given that all major classes of chemotherapeutic drugs are associated with dose-limiting toxicities, some of these have since been tried and tested (and in some cases rejected) as an antibody drug conjugate. The first generation of experimental ADCs often incorporated cytotoxic drugs such as Methotrexate (an inhibitor of dihydrofolate reductase) http://cancerres.aacrjournals.org/co.../3330.full.pdf , Vinblastine http://www.ncbi.nlm.nih.gov/pubmed/2784353 (a plant-alkaloid and microtubule inhibitor), or Doxorubicin (a DNA intercalating drug that inhibits topoisomerase II), drugs which are still commonly used on their own to treat various types of cancers. Although, encouraging results were obtained initially in pre-clinical studies with these early ADCs, they required high doses to be administered in order to achieve significant anti-tumour activity. To increase the potency of these first generation ADCs, a range of methods were employed including increasing the drug:antibody ratio by utilising branched linkers or direct conjugation. While these methods were able to increase the potency of early ADCs to some extent, results from phase I and phase II clinical trials have demonstrated that these early types of conjugated drugs are unlikely to yield objective responses within cancer patients http://www.ncbi.nlm.nih.gov/pubmed/11069223 .

Schematic diagram representing an Antibody
Drug Conjugate (ADC) attached to Doxorubicin
via a hydrazone linker (e.g. Milatuzumab-Dox
developed by Immunomedics)

The first ADC licensed for clinical use, Gemtuzumab Ozogamicin (Mylotarg; Pfizer (previously Wyeth)) was approved by the FDA in 2000 for the treatment of relapsed acute myelocytic leukemia in adults. The cytotoxic compound that is arming this ADC is called N-acetyl-g-calicheamicin which binds in the minor groove of DNA and consequently causes double strand DNA cleavage which results in target cell death.
A highly potent and more recent version of such a minor groove binder are a class of drugs called Duocarmycins (developed by Synthon, e.g. ADC SYD985).

The cytotoxicity of maytansine analogues, such as DM1, DM4, or monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) compounds is realised because of their ability to obstruct cell division by inhibiting tubulin. This inhibition of tubulin arrests target cells in the G2/M stage of the cell cycle which results in apoptosis (cell death). These very potent drugs on their own (which kill tumour cells at sub-nanomolar concentrations), will indiscriminately destroy both healthy and diseased tissue by stopping mitosis. Hence, accurate targeting is required to realise the full potential of these new cancer drugs.

To put this in context, highly potent cytotoxics such as calicheamicins, maytansinoids, auristatins, and duocarmycins are 100 to 1000 times more potent than the first generation drugs used to create ADCs (e.g. Doxorubicin, or Vinblastine, etc...). Most of these potent cytotoxic compounds had failed clinically as free drugs because they were simply too toxic for use in humans. Hence, chemically coupling them to monoclonal antibodies to precisely target tumour tissue provides a means to clinically exploit the potency of these drugs. Below I have included diagrams of the structures of drugs and linkers that are currently being investigated in clinical trials, including some examples.
The duocarmycin analogues are extremely cytotoxic members of a small group of natural products that are able to exert their mode of action at any phase in the cellular cycle (Duocarmycins were first isolated from Streptomyces bacteria in 1988). These synthetic small-molecules are DNA minor groove binding alkylating agents that cause irreversible alkylation of DNA. This alkylation of DNA disrupts the nucleic acid architecture, which eventually leads to tumour cell death. As mentioned earlier, unlike tubulin binders, which will only attack tumour cells when they are in a mitotic state, Duocarmycins work at any phase of cell cycle. Recent research suggests that DNA damaging agents, are more efficacious in killing cancer cells than tubulin binders, especially solid tumours.

Duocarmycins have a potency in the low picomolar range (i.e. extremely little is needed to kill cells), which maximizes the cell-killing potency of antibody-drug conjugates that utilise this compound. In pre-clinical tests a new ADC linked to Duocarmycin called SYD985 (Synthon) outperformed another ADC conjugated to DM1 (Kadcyla developed by Roche/Genentech) in a breast cancer study. Both ADCs utilise an anti-HER2 monoclonal antibody called Trastuzumab to which their respective drugs are conjugated.

Schematic diagram representing an Antibody Drug Conjugate (ADC) attached to Duocarmycin (e.g. an ADC such as SYD985 developed by Synthon)

In addition, Duocarmycins have shown activity in a variety of Multi-Drug Resistant (MDR) tumour cells (e.g. potent cytotoxicity has been observed in cells that express the P-glycoprotein (P-gp) efflux pump). Multi-drug resistance can be a significant problem in the clinical setting (particularly in end-stage terminal cancer patients). Compounds which are less susceptible to these mechanisms of drug resistance are likely to be more successful in the prolonged successful treatment of terminal cancer patients.
Calicheamicins also bind to the minor groove of DNA which results in double strand breaks in DNA and apoptosis (cell death). Again, this DNA binder is also extremely cytotoxic and is active at sub picomolar concentrations.

An example of an ADC that is chemically coupled to Calicheamicin is called Gemtuzumab ozogamacin (Mylotarg). In this instance calicheamicin is conjugated to a humanized anti-CD33 mAb via a hydrazone linker (see figure on the left).

This compound is extremely potent and demonstrated antigen-specific activity in preclinical models at doses of approximately 100 μg/kg.

Gemtuzumab ozogamacin received accelerated approval from the FDA in 2000 for the treatment of CD33-positive Acute Myeloid Leukemia (AML). However, this ADC was voluntarily withdrawn from the market in 2010.

Schematic diagram representing an Antibody Drug Conjugate (ADC) attached to
Calicheamicin (e.g. ADCs such as Inotuzumab ozogamycin and Gemtuzumab
ozogamycin (Mylotarg) originally developed by Wyeth (now part of Pfizer)

Maytansinoids DM1 and DM4

Encouraging clinical trial data have been reported for Trastuzumab Emtansine (also known as Kadcyla or T-DM1), an antibody-drug conjugate that utilises a monoclonal antibody called Trastuzumab which is chemically linked to a maytansinoid drug. Maytansine, including its analogs (maytansinoids), are potent microtubule-targeting compounds that inhibit proliferation of cells that are in the mitotic phase of the cell cycle. DM1 and DM4 are benzoansamacrolides which are derived from ansamitocin. These derivatives differ in steric hindrance around the disulfide bridge. Antibody-maytansinoid conjugates which consist of maytansinoids (DM1 or DM4) that are attached to tumor-specific antibodies can be seen to the left and right of the text in this section. The maytansine linkers are chemically coupled through the amino groups of mAb lysine residues.

Conjugated maytansinoids (once released) potently inhibits breast cancer cell proliferation at sub-nanomolar concentrations, by arresting the cells in the mitotic pro-metaphase / metaphase. Given that T-DM1 utilises a non-cleavable linker it is thought that drug release from the ADC happens as a result of degradation of the antibody (Trastuzumab) inside lysosomes. Blocking of cell cycle progression occurs in concert with the internalization and intracellular processing of ADCs, which induces abnormal mitotic spindle organisation and suppresses microtubule dynamic instability. It is thought that microtubule depolymerisation only occurs at much higher drug concentrations.

Schematic diagram representing an Antibody Drug Conjugate
(ADC) attached to DM1 via a non-cleavable linker

Genentech has licensed the drug and linker technology (DM1 and N- sucinimidyl 4-(maleimidomethyl) Cyclohexane, a thioether linkage via lysine residues) for their antibody from ImmunoGen and Seattle Genetics. Trastuzumab emtansine is targeted for use in patients with advanced HER2-positive breast cancer. Clinical trial data indicates that Trastuzumab Emtansine is stable in circulation for at least 7 days after administration and that it is superior to standard treatment.
In addition to non-cleavable Maytansinoid drug conjugates, cleavable linkers in combination with DM4 are also being studied in clinical trials (E.g. IMGN853 and SAR3419). SAR3419 consists of a humanized antibody that is coupled to DM4 using a cleavable hindered disulfide linker. SAR3419 is targeted at patients with lymphoma (several lymphoma types, please see list and links to clinical trials at the bottom of this article). SAR3419 is currently undergoing phase II clinical trials.

Schematic diagram representing an Antibody Drug Conjugate (ADC)
attached to DM4 via a cleavable linker (e.g. SAR3419 developed by
Sanofi Pasteur or IMGN853 from Immunogen)

IMGN853, developed by ImmunoGen, is composed of an anti-FOLR1 antibody conjugated to the cytotoxic maytansinoid, DM4, via a disulfide-containing linker, SPDB, derived from the experimental antibody drug conjugate M9346A-sulfo-SPDB-DM4. IMGN853 is targeted at patients with ovarian cancer or other solid tumours that over-express FOLR1 (this is also known as Folate Receptor alpha), including Non-Small Cell Lung Cancer (NSCLC). The linker in IMGN853 serves a dual purpose. It is meant to keep the DM4 stably attached to the antibody while the compound is in the bloodstream, but also to optimise release of the drug once it has been internalised. Pre-clinical studies have demonstrated that this combination of linker and maytansinoid drug is superior to other constructs that utilise either DM1 or DM4 as the conjugated drug.

The Auristatins (MMAE and MMAF)
The auristatin analogs, MonoMethyl Auristatin E (MMAE) and MonoMethyl Auristatin F (MMAF) are derived from pentapeptides, called dolastatin 10, found in D. auricularia, a small sea mollusc). The bind to tubulin and inhibit mitosis. Dolastatin 10 is much more potent than Vinblastine and is cytotoxic (kills cells) at subnanomolar concentrations.

The majority of ADCs that are currently undergoing clinical trials belong to this class of drugs. Most developers that use MMAE as the conjugated drug, utilise the valine-citrulline (vc) linker to chemically attach MMAE to the monoclonal antibody. Following internalisation by a tumour cell, the linker is cleaved by lysosomal enzymes (e.g. Cathepsin B), which will subsequently release free MMAE. Given that MMAE is able to cross cellular membranes, local bystander killing (cells in close proximity) may occur, even if those cells do not express the antigen to which the conjugated antibody is targeted.

Schematic diagram representing an Antibody Drug Conjugate (ADC)
attached to Mono-MethylAuristatin E (MMAE) via a stable valine-
citrulline dipeptide linker (e.g. Glembatumomab vedotin (CDX-011) which is being developed by Celldex Therapeutics)

Brentuximab vedotin (see the start of this article) is such a vc-MMAE ADC. As mentioned, impressive results have been obtained with this particular ADC in various clinical trials (including complete remissions in terminal cancer patients and objective tumour response rates of 50% were seen in patients treated at the Maximum Tolerated Dose (MTD)(1.8 mg/kg). Interestingly, the antibody on its own was shown to have no effect.

In addition, biotech companies have developed non-cleavable maleimidocaproyl (mc) linked conjugates of the auristatin analog called MMAF. The mc linker attaches MMAF to solvent accessible thiols present in mAb cysteines. As such, it is thought that MMAF is released following degradation of the antibody in the lysosomal compartment (i.e. after the ADC has been internalised by a cancer cell). Interestingly, the MMAF drug is unable to cross cellular membranes and as a consequence bystander killing is unlikely to occur.
Examples of MMAF conjugated ADCs would be SGN-CD19A or SGN-75 (although SGN-75 has been discontinued by Seattle Genetics and is superseeded by SGN-CD70A (a PBD dimer based ADC (pyrrolobenzodiazepines (PBD) dimers, are derived from a toxin originally isolated from various Streptomyces and are developed by Spirogen)). SGN-CD19A is targeted at patients with various types of lymphoma and is currently undergoing phase I clinical trials (please see list with links at the bottom of this article).

More ADC variants are expected to enter phase I clinical trials in the near future. Some of the new compounds to look out for are Duocarmycins developed by Synthon (as mentioned earlier in the text), but also compounds such as PBD dimers developed by Spirogen which has signed licensing agreements with Genentech and Seattle Genetics. Apparently, they also have a number of additional collaborations with unnamed pharma and biotech companies. Spirogen says that its PBDs can incorporate a wide variety of linker and conjugation chemistries. Two PBD based ADCs are currently in Phase 1 trials, including SGN-CD33A from Seattle Genetics.
Another company, called Heidelberg Pharma, has developed a potent RNA polymerase inhibitor from a mushroom with the name Amanita phalloides, while Viventia Biotechnologies has developed a de-immunised form of a bouganin protein toxin that is derived from the leaves of Bougainvillea spectabilis.

Schematic diagram representing an Antibody Drug Conjugate (ADC)
attached to MMAF via a non-cleavable Maleimido Caproyl linker (e.g.
SGN-CD19A developed by Seattle Genetics)

List of Antibody Drug Conjugates (ADC) for the treatment of cancer currently (2014) undergoing clinical trials. Please see the list
with links to clinical trials below.

ADC & clinical trial link
1 IGN523
2 DEDN6525A (RG7636)
3 Anti-MUC16 (DMUC5754A, RG7458)
4 Anti-NaPi2b (DNIB0600A, RG7599)
5 Anti-STEAP1 (DSTP3086S, RG7450)
6 Pinatuzumab vedotin (Anti-CD22, DCDT2980S, RG7593)
7 Polatuzumab vedotin (Anti-CD79b, DCDS4501A, RG7596)
8 Trastuzumab emtansine [Kadcyla], trastuzumab-MCC-DM1, T-DM1
9 IMGN853
10 SGN-CD19A
11 SGN-CD70A (superseding SGN-75)
12 Brentuximab vedotin (SGN35, ADCETRIS)
13 SGN-CD33A
15 ASG-22ME / ASG-22M6E
16 ASG15E-13-1 (ASG-15ME)
17 Inotuzumab ozogamicin
18 SAR3419
19 SAR566658
20 SYD985
21 HuMax-TF-ADC (TF-011-MMAE)
22 BT-062
23 Glembatumomab vedotin (CDX-011)
25 IMGN289 (J2898A)
26 Lorvotuzumab mertansine
27 Milatuzumab-dox
28 SGN-75
29 AGS-16M8F
30 BAY-94-9343
31 BIIB015
32 IMGN529 (K7153A)
33 IMGN853 (M9346A)
34 IMMU-130 (hMN-14-SN38 / Labestuzumab-SN-38)
35 IMMU-132 (hRS7-SN38 ADC)
36 MLN0264
37 AMG 595
38 AMG 172
39 PF-0626350
40 SC16LD6.5
41 Gemtuzumab ozogamicin
42 ASG-5ME
43 Bay 79-4620
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Old 15-06-2014, 07:21 AM   #602
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Teaching our immune system to kill glioblastoma: an interview with Dr Keith L. Black

Typically brain tumours outwit our immune system, by being invisible to it. Sarah McKay talks to world–renowned neurosurgeon and neuroscientist Keith Black from Cedars-Sinai Medical Centre, LA about fighting GBM with immunotherapy.

Despite recent advances in treatment by combination surgery, radiotherapy, and chemotherapy, the outlook for patients with glioblastoma remains grim. One of the main reasons leading to such poor prognosis is the fact that these brain tumours are able to grow within the brain undetected by the immune system.

“I believe the next big thing in brain tumour research will focus on teaching the immune system how to eradicate tumours”

- Dr Keith L. Black, MD, chair and professor of Cedars-Sinai's Department of Neurosurgery.

Dr Black and his team have developed a vaccine (ICT-107) that alerts the immune system to the existence of glioblastoma and activates a tumour-killing response. “We administer a therapy to allow immune cells, which are capable of killing tumours, to see tumours that were previously invisible to the immune system”

ICT-107 showed promising results in Phase I trials when patients were treated with the vaccine as well as undergoing the standard therapy of surgical resection, regular radiation therapy and chemotherapy. ICT-107 was given to 16 newly diagnosed glioblastoma patients—of the 16, six patients showed no evidence of tumour recurrence and were free of disease up to five years after treatment. The median survival was 38.4 months, significantly longer than the typical 14.6-month survival of patients with newly diagnosed glioblastoma receiving standard therapy alone.

The ICT-107 vaccine is made from a particular type of immune cell called a dendritic cell that is isolated from a patient’s blood. Dendritic cells are responsible for presenting the antigens (or ‘scent’) of an undesirable cell (virus, bacteria or cancer cell) to the immune system’s cancer fighting T-cells.

To make ICT-107, dendritic cells are loaded with the scent of six proteins (HER2/neu, TRP-2, gp100, MAGE-1, IL13R2 and AIM-2) all involved in the development of glioblastoma. When re-injected under the skin of patient, the dendritic cells activate the patient’s own T-cells, which, in turn, recognise and destroy any lingering glioblastoma cells.

The trial has now moved on to a Phase II placebo controlled trial in 25 different centres in the US. Dr Black reports that the results from the Phase II trial haven’t been quite as promising as Phase I, but notes that it is still early days. “Our top line results were reported last December. What they are showing is there is a significant increase in progression free survival for patients treated with the vaccine. And that’s very positive because very few treatments can improve progression free survival for glioblastoma. Overall survival was increased by two to three months, but didn’t reach statistical significance.”

But Dr Black is optimistic. “This study was small and this is an early read-out. What we did see in Phase I were a number of long-term survivors. So, it’ll be important to see some longer-term read-outs from this trial to see if the survival reaches statistical significance.”

Although the vaccine is not available in Australia, Dr Black believes the likelihood of bringing these strategies to Australia are high. "Collaborating with centres here in Australia for clinical trials would be very likely.” An earlier version of the vaccine, DCVax made by activating dendritic cells with proteins taken from a patient’s brain tumour, has recently been licensed for use in Germany.

Dr Black is building on his success with vaccine strategies and new research is focussing on combination treatments, which combine dendritic cell vaccines with the use of ‘check-point inhibitors’.

“Check-point inhibitors are big news in melanoma and lung cancer, and we might be to apply some of that knowledge to brain tumours.”

- Dr Keith L. Black, MD.

The best-known example of a checkpoint protein is PD-L1 (for Programmed Death Ligand 1 and its receptor is PD-1). The body needs PD-L1 to keep T-cells from attacking healthy cells. To evade detection, cancer cells may up-regulate (speed up the production of) PD-L1 as a shielding mechanism. Checkpoint inhibitors work against checkpoint proteins to expose the shielded cancers to T-cells without causing immune cells to attack healthy tissue.

Dr Black is very optimistic about this combination strategy, “It becomes a one-two punch. Because it teaches the immune cells how to become activated against the cancer, and the checkpoint inhibitors are essentially releasing the brakes on the T cells and hyping them up.”

Australia is internationally renowned for having significant immunology research talent and the Foundation has identified immunology as one of four key research areas for funding. This is why, amongst others, we are supporting Associate Professor Gilles Guillemin and his work on the ‘Kynurenine Pathway Project’ being undertaken in the Neuroinflammation research group at Macquarie University. The aim of the research is to understand the way tumour cells use the kynurenine pathway to neutralise the immune system, and prevent the immune cells from destroying glioblastoma.

In May, Cure Brain Cancer Foundation will be hosting an international scientific meeting in Sydney, including many senior figures in the field of neuro-oncological research from around the globe, to promote collaboration and accelerate research outcomes. The meeting will be addressed by Australian researcher Dr Ian Frazer, who developed and patented the basic technology behind the HPV vaccine against cervical cancer; the second cancer preventing vaccine, the first vaccine designed to prevent a cancer and a major breakthrough in immunotherapy.

Like Dr Black, we also believe immunology will play a major role in accelerating treatments and ultimately meeting our bold mission to increase five-year survival to 50% within 10 years.

Dr Sarah McKay, Medical Writer and Neuroscientist

Reference for Phase I info:

Surasak Phuphanich, Christopher J. Wheeler, Jeremy D. Rudnick, Mia Mazer, HongQian Wang, Miriam A. Nuño, Jaime E. Richardson, Xuemo Fan, Jianfei Ji, Ray M. Chu, James G. Bender, Elma S. Hawkins, Chirag G. Patil, Keith L. Black, John S. Yu.

Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunology, Immunotherapy, 2012; DOI: 10.1007/s00262-012-1319-0


{KEITH BLACK** One of the things we know that cancer does in general, and brain tumours do specifically, is that they make themselves invisible to the immune system. And the tumour also begins to release things in the environment around the tumour, to try to kill an immune response. So the vaccine is designed really for two things. One, it’s designed to allow the immune system to recognise the tumour and mount an immune response against it, and to try to eradicate those cells. We take a very specialised immune cell, called a dendritic cell, that is very useful in processing proteins that it samples throughout the body, we load those dendritic cells with the scent, or the tumour proteins, those dendritic cells are then able to present those bad tumour proteins to killer T cells, that then become activated and divide into millions of cells, and then go throughout the body – in this case specifically the brain – to try to find the tumour cells and kill the tumour cells.

SARAH** What would be the likelihood of bringing some of this to Australia?

{KEITH** I think the chances of bringing these strategies to Australia would be very high, the ICT-107 trial where we’ve had the best results has not been approved for use yet, but I think collaborating with centres here in Australia for clinical trials, would be very likely.

{SARAH** I’m wondering if you think there’s a next big thing in brain tumour research?

{KEITH** I believe that the next big thing in brain tumour research will try to focus on teaching the immune system how to eradicate the tumour, because drug therapy, target therapy, we think is going to be very difficult. I think we will build on our success with vaccine strategies and then also use some of these breakpoint inhibitors, like the PD1, PDL1 antibodies, the CD4 antibodies that made really big news last year in cancer treatment for things like melanoma and lung cancer, I think you will begin to see us apply some of those to brain tumours and apply them in combination with vaccine strategies, which I remain very confident about, because it becomes a one-two punch. The vaccine teaches the immune cells to become activated and these antibodies called checkpoint inhibitors like PD1, PDL1, CD4 antibodies, are essentially releasing the brakes on the T cell that make them super hyped-up, so they go in and try to eradicate the cancer cells.

{SARAH** Are there any particular types of brain cancer where you think there’s a bit more hope?

{KEITH** One of the areas that I think would be particularly exciting would be in the area of Low Grade Gliomas. During the course of the disease about 80 – 95 per cent will convert to High Grade Gliomas, the grade three and grade four gliomas, so here we have an opportunity to get ahead with vaccine strategies, with immune strategies, to be able to teach the immune system what those tumours will become and to try to eradicate those cells at a very early stage. The challenge will be that it’s a smaller group of patients that have a longer survival so the trials will be more expensive and will require collaborations of multiple centres. And then the second major barrier, unfortunately, will be the financial incentive of drug companies to develop these strategies. But I think that’s where we have probably the greatest opportunity.

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Old 15-06-2014, 07:53 AM   #603
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NeuVax, developed by Galena Biopharma, Inc., is a peptide-based vaccine aimed at preventing or delaying the recurrence of breast cancer in cancer survivors who achieve remission after standard of care treatment (e.g., surgery, radiation, chemotherapy). It consists of the E75 synthetic peptide initially isolated from HER2/neu proto-oncogene combined with the immune adjuvant, granulocyte macrophage colony stimulating factor (rhGM-CSF from yeast). NeuVax works by harnessing the patient’s own immune system to seek out and attack any residual cancer cells that express HER2/neu, a protein associated with tumors in breast, ovarian, pancreatic, colon, bladder and prostate cancers.
Clinical trials[edit]

NeuVax has been tested as adjuvant treatment in nearly 200 breast cancer patients over a total of 5 years, and has shown to be safe and effective in Phase 2 trials. As a result, two additional NeuVax trials underway are: (1) a 700 patient Phase 3 trial for FDA approval and (2) a 300 patient Phase 2 trial studying the combination of NeuVax and Herceptin® (trastuzumab).

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Old 16-06-2014, 05:50 AM   #604
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DCVax® – L

Our lead product is DCVax-L for Glioblastoma multiforme (“GBM”), the most lethal form of primary brain cancer. We have completed two Phase I/II trials and are now well under way with a large Phase III trial, as described below.

With full standard of care treatment for GBM today, including surgery, radiation and chemotherapy, the median time from surgery to remove the initial tumor to the time of tumor recurrence is just 6.9 months, and median survival is just 14.6 months. There has been very little improvement in clinical outcomes for GBM patients in the last 30 years. The incidence of GBM appears to be on the rise, for unknown reasons, and there is an urgent need for new and better treatments.

Our Prior Phase I/II DCVax-L Trials for GBM

We, together with our collaborator, Dr. Linda Liau, conducted two prior Phase I/II clinical trials at UCLA with DCVax-L for GBM brain cancer. Those trials consisted of 39 patients, including 20 patients with newly diagnosed GBM and 19 patients recurrent GBM and other gliomas. The newly diagnosed patients who received DCVax in addition to standard of care treatment typically did not have tumor recurrence for a median of approximately 2 years (more than triple the usual time with standard of care treatments), and they survived for a median of approximately 3 years (about 2½ times the usual period of survival with standard of care treatment).

Furthermore, a substantial percentage of patients who received DCVax-L in the prior Phase I/II clinical trials have continued in a “long tail” of survival far

beyond even the 3 year median survival. As of the latest long-term data update in July, 2011, 33% of the patients had reached or exceeded 4 years’ median survival and 27% had reached or exceeded 6 years’ median survival. As of this year, 2 of the Phase I/II clinical trial patients have exceeded 10 years’ survival (compared with 14.6 months’ median survival with full standard of care treatment today).

Our Current Phase III Trial

We are currently conducting a 312-patient double blind, randomized, placebo controlled Phase III clinical trial with DCVax-L for newly diagnosed GBM. The primary endpoint of the trial is “Progression Free Survival,” meaning the length of time that a patient continues without disease progression (i.e., recurrence of the tumor). Secondary endpoints include overall survival and other measures.

The trial is under way at 51 sites (medical centers) across the US. The sites and the eligibility criteria are listed in the profile of the trial on www.clinicaltrials.gov. The trial is also under way in Europe. The lead site is Kings College Hospital in London. Approximately 30 trial sites are also in varying stages of preparation in the U.K. and Germany.

DCVax® – Direct

Our DCVax-Direct product offers a potential new treatment option for the wide range of clinical situations in which patients’ tumors are considered “inoperable” because the patient has multiple tumors, or their tumor cannot be completely removed, or the surgery would cause undue damage to the patient and impair their quality of life.

A large number of patients with a variety of cancer types (including lung, colon, pancreatic, liver, ovarian, head and neck, and others) are faced with this situation, because their tumors are already locally advanced or have begun to metastasize by the time symptoms develop and the patients seek treatment. For these patients, the outlook today is bleak and survival remains quite limited.

DCVax-Direct is administered by direct injection into a patient’s tumors. It can be injected into any number of tumors, enabling patients with locally advanced disease or with metastases to be treated. DCVax-Direct can also be injected into tumors in virtually any location in the body: not only tissues at or near the surface of the body but also, with ultra-sound guidance, into interior tissues.

We are currently conducting a 60-patient Phase I/II trial of DCVax-Direct for all types of inoperable solid tumors. The trial is under way at MD Anderson in Houston, TX and MD Anderson in Orlando, FL, with additional sites in varying stages of preparation. The eligibility criteria can be found in the profile of this trial on www.clinicaltrials.gov. The Phase I stage of the trial involves dose escalation, testing 3 different dose levels of DCVax-Direct, and confirmation of the optimal dose. The Phase II stage of the trial will focus on efficacy. The primary measure of efficacy will be regression (i.e., shrinkage or elimination) of the patient’s existing inoperable tumors. Such regression is a rapid endpoint: if it is going to occur, is anticipated to occur within a couple months of treatment.

DCVax® – Prostate

DCVax®-Prostate is designed specifically for late stage, hormone independent prostate cancer. Such cancer involves the spread of micro-metastases beyond the prostate tissue. In most patients, there is no focal tumor which can be surgically removed and used to make lysate, or into which dendritic cells can be directly injected. Instead, the cancer cells are diffuse. We have developed a DCVax product line using a particular proprietary antigen — PSMA (Prostate Specific Membrane Antigen) — which is found on essentially all late stage (hormone independent) prostate cancer. The PSMA is produced through recombinant manufacturing methods, and is then combined with the fresh, personalized dendritic cells to make DCVax-Prostate.


ICT-107 is an autologous (patient-derived) dendritic cell (DC) vaccine that targets six different antigens (peptides that are tumor markers) associated with glioblastoma multiforme (GBM), the most common and lethal form of brain cancer. Four of the tumor-associated antigens are highly expressed on cancer stem cells (CSCs). ICT-107 is designed for use following surgical tumor resection and in combination with standard treatment with radiation and chemotherapy.

Results from our phase I trial showed that patients with newly diagnosed GBM treated with ICT-107 experienced a meaningful survival benefit compared with historic standard of care. The median progression-free survival (PFS) in the 16 patients enrolled in the trial was 16.9 months, and median overall survival (OS) was 38.4 months – a 20-month improvement compared to historic standard of care in similar patients. Updated data from this trial presented in November 2013 showed that eight of 16 patients survived longer than five years after diagnosis. Seven of the 16 participants were still living, with length of survival ranging from 60.7 to 82.7 months after diagnosis. Six of the patients also were progression-free for more than five years, meaning the tumors did not return or require more treatment during that time. Four participants still remained free of disease with good quality of life at lengths ranging from 65.1 to 82.7 months following diagnosis. ICT-107 was shown to be generally safe and well tolerated, with no significant adverse events reported.

We completed a randomized, double-blind, placebo-controlled, multicenter phase II clinical trial in 124 patients with newly diagnosed GBM in 2013. A top-line data read-out from this trial was reported in December 2013. Updated results, including data on pre-specified subgroup and immunological analyses from the phase II trial, were presented at the ASCO annual meeting in June 2014.

The data reported in December 2013 demonstrated a statistically significant increase in PFS, a key secondary endpoint. The trial did not achieve its primary endpoint of OS. A comparison of PFS between ICT-107 and placebo showed a statistically significant difference in the Kaplan-Meier (K-M) curves favoring ICT-107 (p=0.014 two-sided, hazard ratio (HR)=0.56) in the intent-to-treat population (ITT) of all 124 randomized patients. The difference in the median PFS times between ICT-107 and placebo favored ICT-107 and was 2 months in duration. For the per-protocol (PP) population (117 of 124 patients receiving at least 4 induction vaccinations), the K-M comparison p-value improved in treated patients to 0.0074 two-sided (HR=0.53) and the difference in median progression-free survival times increased to 3 months in favor of ICT-107.

The differences in the OS K-M curves did not reach statistical significance in the ITT population (the primary endpoint) or the PP population, with p-values and HRs of p=0.58 two-sided, HR=0.87, and p=0.40 two-sided, HR=0.79, respectively. However, there were numerical differences in the median survivals favoring ICT-107 of two months in the ITT population and three months in the PP population.

The OS analysis included data on 67 events (patient deaths) out of a possible 124, whereas the PFS analysis included data from 103 events. ICT-107 was generally safe and well tolerated, with no imbalance of adverse events between the active and placebo groups.

The updated ICT-107 phase II data presented in June 2014 showed that when OS and PFS were assessed in pre-specified patient subgroups, results favored treatment with ICT-107 over control in HLA-A2 patients within each of the 2 major MGMT subgroups (unmethylated and methylated). While the subgroups were small in size, and not powered to show statistical significance, the numeric advantages in favor of ICT-107 treated patients were shown to be large and clinically meaningful.

In the PP analysis of data from HLA-A2 patients with unmethylated MGMT: The control and treated median OS times were 11.8 and 15.8 months, respectively, indicating about a 4-month or 33% numeric survival increase for treated patients (HR=0.612, log-rank p-value=0.175);

The median PFS times for control and treated patients were 6.0 and 10.5 months, respectively, indicating about a 4.5-month or 75% numeric PFS increase for treated patients (HR=0.758, log-rank p-value=0.442);

There were also signs of a potential long-term survival benefit for ICT-107-treated patients, with 21% of treated patients still alive compared to only 7% of controls.

In the PP analysis of data from HLA-A2 patients with methylated MGMT:

The control and treated groups had still not reached median survival times as of the time of data analysis, with the majority of patients still alive (65% of treated compared to 57% of control patients); However, the median PFS times for control and treated patients were 8.5 and 24.1 months, respectively, indicating about a 15.6-month or 184% statistically significant PFS increase for treated patients (HR=0.259, log-rank p-value=0.005).

The data presentation at ASCO was based on about 17.6 and 16.2 months of median follow-up for ICT-107 and control patients, respectively. As of April, a total of 79 events had been recorded, representing 12 additional events since the data were reported in December 2013. 30 active and 15 control patients were alive for a total of 45 patients available for additional follow-up.

Median OS in the ITT updated results was 18.3 months for ICT-107 and 16.7 months for control, representing a numeric advantage for the treatment group of 1.6 months (HR=0.89, p-value=0.643). In the PP population, median OS was 18.6 months for ICT-107 and 16.7 months for control, representing a numeric advantage for the treatment group of 1.9 months (HR=0.84, p-value=0.477).

Median PFS in the ITT updated results was 11.2 months for ICT-107 and 9.0 months for control, representing a statistically significant advantage for the treatment group of 2.2 months (HR=0.57, p-value=0.011). In the PP population, median OS was 11.4 months for ICT-107 and 9.0 months for control, representing a statistically significant advantage for the treatment group of 2.4 months (HR=0.54, p-value=0.006).

Both the OS and PFS median results in the ICT-107 phase II trial were measured from the time of randomization (i.e., at the start of vaccination after standard-of-care surgery and chemoradiation). In historical studies of newly diagnosed GBM patients (e.g., Stupp, et al.), OS and PFS measurements were likely assessed from the time of surgery. In the ICT-107 phase II trial, there was an average of about 83 days from surgery to randomization.

Vaccine potency was assessed via measurements of key dendritic cell indicators of cell maturity and activation and their correlation with survival time. Two key indicators relating to IL-12 secretion and HLA-DR expression were predictive of survival in all treated patients in the results announced in December. In the updated results, IL-12 secretion and HLA-DR expression were again correlated with treated patient survival time in Cox Proportionate Hazards models, with p-values of 0.048 and 0.006, respectively.

We are in the process of finalizing the design of the phase III protocol, in anticipation of discussions with the FDA and the European Medicines Agency, or EMA. Plans are underway to request an end-of-phase II meeting with the FDA, anticipated to take place during the summer. Following typical European protocol in preparation for meeting with the EMA, we have requested advice meetings at the national level in Germany, the UK and the Netherlands to discuss ICT-107. These meetings are scheduled to take place later in June. In the third or fourth quarter of 2014, we plan to seek advice from the EMA on the approval process for ICT-107.

We also plan to continue to monitor patients in the phase II trial and update the data analysis at upcoming scientific meetings.

ICT-107 has been granted orphan drug designation in the US and Europe.

ICT-121 is a DC vaccine that targets CD133, an antigen commonly associated with CSCs. Because most solid tumors include CSCs that express CD133, ICT-121 has potential to be used to treat a variety of tumor types. We are supporting an open-label, physician-sponsored phase I clinical trial of ICT-121 in approximately 20 patients with recurrent GBM at Cedars-Sinai Medical Center. The primary objective of the trial is to assess the safety and tolerability of ICT-121. Secondary objectives include measuring overall survival and progression-free survival at six months after surgery, as well as other response parameters. Patients will receive the vaccine once per week for four weeks during the induction phase, followed by a maintenance phase consisting of one treatment every two months until their supply of vaccine is depleted or they experience progressive disease.

ICT-140 is an autologous DC vaccine that targets seven different antigens associated with ovarian cancer, including ones expressed by CSCs. We plan to conduct an open-label, randomized exploratory phase II clinical trial at four clinical sites in the US. Thirty patients with ovarian cancer who are at high risk of having a first recurrence will be enrolled. Twenty patients will be treated with standard of care plus ICT-140, while 10 will constitute a comparator group who will only receive standard of care. Should the results from the first cohort of patients support further enrollment, we will randomize another 20 patients to be treated, plus 10 more comparator patients. The phase II trial is anticipated to begin 3Q 2014.

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Old 16-06-2014, 06:59 AM   #605
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DCVax-Direct Trial Update Indicates Further Positive Responses; 3 Case Studies Show No Live Tumor Cells In Injected Tumors

All 9 Out Of 9 Patients Who Have Reached 4 Injections Are Showing Tumor Cell Death, Tumor Shrinkage And/Or Stabilization Of Disease

BETHESDA, Md., June 11, 2014 – Northwest Biotherapeutics (NASDAQ: NWBO) (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, announced today that, in the ongoing Phase I/II clinical trial of DCVax-Direct for all types of inoperable solid tumors, all 9 out of 9 patients who have received 4 of the 6 planned injections are showing tumor cell death, tumor shrinkage, substantial immune cell accumulation in their tumors and/or stabilization (i.e., stopping the progression) of their advanced cancer. In addition, in 3 of these 9 patients, biopsies now show no live tumor cells in the injected tumor.

To date, 20 patients (including the 9 referenced above) have received at least 3 of the 6 total injections, and 13 of these 20 patients are showing tumor cell death, tumor shrinkage, substantial accumulation of immune cells in the tumors, and/or stabilization of their disease. The Company plans to report more details when the patients are further along in the treatment regimen. The first 3 injections are given in the first 2 weeks of the 32-week treatment regimen (at Day 0, Day 7 and Day 14).

So far, 9 of the patients have received 4 of the 6 planned injections, and all 9 of these 9 patients are showing tumor cell death, tumor shrinkage, substantial accumulation of immune cells in the tumors, and/or stabilization of the patients’ disease. The 4th injection is administered in week 8 of the 32-week treatment regimen. (The overall treatment regimen includes 6 injections at Days 0, 7 and 14, and Weeks 8, 16 and 32.)

Also, in a new finding, biopsies taken in 3 of these 9 patients now show no live tumor cells in the tumor that was injected. These 3 cases include diverse, advanced and particularly aggressive cancers: 1 metastatic pancreatic cancer case, 1 metastatic colon cancer case and 1 metastatic sarcoma case. These patients’ tumors show some enlargement on imaging scans, but the biopsies show that live tumor cells are no longer detectable and immune cells are now found there. Each of these 3 patients was treated with the lowest dose level (2 million cells per treatment).

In these 3 patients, as well as the other patients in the trial, only one of their tumors has been injected with DCVax-Direct. The Company plans to inject multiple tumors in its further studies of DCVax-Direct.

“These early glimpses are indicating an increasingly encouraging picture – especially the absence of any live tumor cells in 3 of the patients who have received 4 of the 6 planned injections of DCVax-Direct,” commented Linda Powers, CEO of NW Bio. “The 4th injection is still quite early, as it is just 8 weeks into the 32-week treatment regimen. For patients with such advanced, metastatic, inoperable cancers, who have failed other existing treatments, these are exciting findings.”

“We are also quite encouraged to see the patients’ reactions growing as the treatments progress,” noted Ms. Powers. “As of the 3rd injection in week 2 of the treatments, we now have 65% of the patients (13 of 20) showing some positive effects, and as of the 4th injection in week 8 of the treatments, we now have 100% of the patients (9 of 9) showing some positive effects. The patients also report feeling significantly better.”

“Patience will be important as we move through the rest of the treatment regimen for all 36 patients in the Phase I portion of the trial, and proceed with the Phase II portion of the trial. The data may get either better or worse as more data is collected. However, something interesting and encouraging seems to be unfolding so far.”

This growing body of initial early data is a result of both imaging scans and biopsies. The 9 patients who have received 4 injections show a range of tumor reactions, from shrinkage to no growth to some enlargement. However, in all of these patients, the biopsies show substantial tumor cell death, and in the cases of enlargement, the biopsies show major infiltration and accumulation of immune cells in and around the tumors – potential indications of an immune response to the cancer.

DCVax-Direct is a personalized immune therapy for all types of inoperable solid tumor cancers, using dendritic cells (the master cells of the immune system) to mobilize the full immune system to attack the patient’s cancer. DCVax-Direct is administered by direct injection into the patient’s tumors, and can reach tumors in virtually any location in the body (with image guidance for interior locations).

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Old 16-06-2014, 12:09 PM   #606
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Blocking Key Energy Protein Kills Cancer Cells, First Evidence Provided

Researchers in Taiwan report for the first time that blocking a key energy-supplying protein kills cancer cells. The finding, described as the first to test possible medical uses of so-called ATP-synthase inhibitors, may lead to new and more effective anti-cancer medications, according to a new report.

In a finding that could lead to more effective anti-cancer medication, scientists exposed breast cancer cells to a substance that blocks a protein called ATP synthase. The cancer cells were killed while normal ones were preserved.

Renergy-supplying protein kills cancer cells. The finding, described as the first to test possible medical uses of so-called ATP-synthase inhibitors, may lead to new and more effective anti-cancer medications, according to a new report.

In the new study, Hsueh-Fen Juan and colleagues focused on ATP synthase, a key protein involved in producing the energy-rich molecules of ATP that power all life processes. For years researchers thought that the protein existed only in mitochondria, structures located inside cells that convert nutrients into energy. Recent studies found high levels of ATP synthase on the surface of cancer cells, but until now the medical implications went unexplored.

The researchers analyzed tissue samples from breast cancer patients and found for the first time that the surface of breast cancer cells contains high levels of ATP synthase. In cell studies, exposing breast cancer cells to a substance that blocks ATP synthase killed the cancer cells but did not harm normal cells, the researchers say. The findings suggest that ATP synthase inhibitors may represent a new approach for fighting breast cancer and other cancer types, they say.



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Old 17-06-2014, 05:34 AM   #607
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Old 17-06-2014, 08:41 AM   #608
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When cells are approaching the Hayflick limit in cell cultures, the time to senescence can be extended by the inactivation of the tumor suppressor proteins - p53 and Retinoblastoma protein (pRb). Cells that have been so-altered will eventually undergo an event termed a "crisis" when the majority of the cells in the culture die. Sometimes, a cell does not stop dividing once it reaches crisis. In a typical situation, the telomeres are shortened, and the integrity of the chromosomes declines with every subsequent cell division. Exposed chromosome ends are interpreted as double-stranded breaks (DSB) in DNA; such damage is usually repaired by reattaching (religating) the broken ends together. When the cell does this due to telomere-shortening, the ends of different chromosomes can be attached together. This temporarily solves the problem of lacking telomeres; but, during anaphase of cell division, the fused chromosomes are randomly ripped apart, causing many mutations and chromosomal abnormalities. As this process continues, the cell's genome becomes unstable. Eventually, either sufficient damage will be done to the cell's chromosomes such that cell dies (via programmed cell death, apoptosis), or an additional mutation that activates telomerase will take place.
With the activation of telomerase, some types of cells and their offspring become immortal; that is, their chromosomes will not become unstable no matter how many cell divisions they undergo (they bypass the Hayflick limit), thus avoiding cell death as long as the conditions for their duplication are met. Many cancer cells are considered 'immortal' because telomerase activity allows them to divide virtually forever, which is why they can form tumors. A good example of cancer cells' immortality is HeLa cells, which have been used in laboratories as a model cell line since 1951.
While this method of modeling human cancer in cell culture is effective and has been used for many years by scientists, it is also very imprecise. The exact changes that allow for the formation of the tumorigenic clones in the above-described experiment are not clear. Scientists have subsequently been able to address this question by the serial introduction of several mutations present in a variety of human cancers. This has led to the understanding of several combinations of mutations that are sufficient for the formation of tumorigenic cells, in a variety of cell types. While the combination varies depending on the cell type, a common theme is that the following alterations are required: activation of TERT, loss of p53 pathway function, loss of pRb pathway function, activation of the Ras or myc proto-oncogenes, and aberration of the PP2A protein phosphatase.[citation needed] That is to say, the cell has an activated telomerase, eliminating the process of death by chromosome instability or loss, absence of apoptosis-induction pathways, and continued activation of mitosis.
This model of cancer in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors that have not activated TERT, most have found a separate pathway to maintain telomere length termed ALT (Alternative Lengthening of Telomeres). The exact mechanism behind telomere maintenance in the ALT pathway has not been made clear, but likely involves multiple recombination events at the telomere.
There have been two telomerase vaccines developed: GRNVAC1 and GV1001. GRNVAC1 isolates dendritic cells and the RNA that codes for the telomerase protein and puts it back into the patient to make the cytotoxic T cells kill the telomerase-active cells. GV1001 comes from the active site of hTERT and is recognized by the immune system and subsequently reacts by killing the telomerase-active cells.

Telomeres and Telomerase and Cancer
Telomerase is upregulated in many tumor progenitor cells, which enables the continued and uncontrolled proliferation of the malignant cells that drive tumor growth and progression. Telomerase expression has been found to be present in approximately 90% of biopsies taken from a broad range of human cancers. Our non-clinical studies, in which the telomerase gene was artificially introduced and expressed in normal cells grown in culture, have suggested that telomerase does not itself cause a normal cell to become malignant. However, the sustained upregulation of telomerase enables tumor cells to maintain telomere length, providing them with the capacity for limitless proliferation. We believe that sustained upregulation of telomerase is critical for tumor progression as it enables malignant progenitor cells to acquire cellular immortality and avoid apoptosis, or cell death. In addition, recent data from studies in malignant melanoma suggest that molecular mutations that result in increased telomerase expression may be early and fundamental driving events for certain types of cancer.

Telomerase Inhibition: Inducing Cancer Cell Death
We believe that inhibiting telomerase may be an attractive approach to treating cancer because it may limit the proliferative capacity of malignant cells. We and others have observed in various in vitro and rodent tumor models that inhibiting telomerase results in telomere shortening and arrests uncontrolled malignant cell proliferation and tumor growth. In vitro studies have suggested that tumor cells with short telomeres may be especially sensitive to the anti-proliferative effects of inhibiting telomerase. Our non-clinical data also suggest that inhibiting telomerase is particularly effective at limiting the proliferation of malignant progenitor cells, which have high levels of telomerase and are believed to be the key drivers of tumor growth and progression.
Many hematologic malignancies are known to arise from malignant progenitor cells in the bone marrow that express higher telomerase activity and have shorter telomeres when compared to normal healthy cells. These disease characteristics support telomerase as a rational and potentially specific oncology target.
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Old 17-06-2014, 09:38 AM   #609
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Chemotherapy vs Immunotherapy
Before I start, I thought it might be useful to remind you of this sobering statistic; World-wide 16 people die every minute, every day from cancer (that means 5 people in North America and Europe die …every minute of every hour of every day from cancer).

The lucky ones that survive often do so at a cost; hence the saying, "If the cancer doesn't kill you, the treatment might". The problem with conventional therapy is the “one size fits all” approach, horrendous side effects, and resistance. As such, it has prompted the need for more personalised and / or alternative cancer therapies in patients with advanced solid tumours. Unfortunately, the list of promising alternatives that potentially constitute a cure is remarkably short. However, recent scientific advances in developing attenuated (genetically modified) Salmonella strains have allowed for the creation of bacterial strains that possibly constitute such a promising alternative strategy.

The role of bacteria in tumour regression and curing cancer was recognised more than a hundred years ago. The German physicians W. Busch and F. Fehleisen separately observed that cancers regressed following accidental erysipelas (Streptococcus pyogenes) infections that occurred whilst patients were hospitalised. It wasn’t until the American physician Dr William Coley noticed that cancer could be cured following an infection with erysipelas, that it became a form of therapy. He developed a safe vaccine, composed of two killed bacterial species, S. pyogenes and Serratia marcescens which stimulates the immune system and induces a fever without incurring the risk of an actual infection. Complete and prolonged regression of advanced malignancy (long term durable remission) was documented in many cases that were treated with Coley’s Toxin (please see the extensive blog post on Coley’s Toxin if you require further information on this immunotherapy). The success of Coley's toxins provided the foundation for current research in this field. Unfortunately, many recently developed immunotherapies (including biologics such as antibodies) are unable to match the well documented cure rate of Coley’s Toxin.

Injection of attenuated Salmonella strain into cancer patient and the effect on tumor growth

Salmonella as a Cancer Fighter

The success of innovative cancer therapies depends in part on their ability to selectively target cancer cells for destruction while limiting toxicity to normal tissues. Since Coley's remarkable achievements, an array of natural and genetically modified bacterial species have been investigated for their potentially tumoricidal properties. Live, genetically modified non-pathogenic Salmonella strains have been created that are capable of multiplying selectively in tumours which in turn inhibits tumour growth while not harming normal cells. In light of their selectivity for tumour tissues, these Salmonella sub species also serve as ideal vectors for transporting therapeutic proteins into cancer cells.
As a consequence of this new development, Salmonella may well be bouncing back from a long time bad reputation. Thus, even though they have generally been feared and despised by humanity, that may be about to change as a result of their cancer fighting cousins.

This table was copied from a publication by Sznol and colleagues
in 2000.

How does Salmonella immunotherapy work?
In line with Coley’s concept of using bacteria in cancer therapies, other bacterial species have over time been evaluated. From these studies it is clear that attenuated Salmonella Typhimurium is one of the more promising candidates. The S. Typhimurium strain and its derivatives have been used for their natural ability to colonise and destroy tumours while some scientists have utilised them as vectors to transport cytotoxic agents.

The attenuated Salmonella Typhimurium strain with which one of the earlier clinical trials was performed is called VNP20009. Initially, researchers demonstrated that this particular genetically modified form of Salmonella had a significant effect on tumour growth in mice. However, VNP20009 used in the treatment of cancer patients (during a phase I clinical trial) lacked the efficacy that was found in mice studies. Nevertheless, this investigation provided necessary evidence that Salmonella is safe for use in cancer patients in a clinical setting.
In order to understand subsequent details about why and how these attenuated Salmonella strains are capable of homing in on tumours and cause subsequent destruction, it is perhaps worthwhile to briefly review some of the basics concepts in terms of life cycle and the genetics that govern these bacteria.

Salmonella belongs to the Enterobactericae family, which is a group of Gram-negative pathogenic, facultative intracellular anaerobic bacteria.
In humans, the Salmonella enterica, subspecies enterica serovars Typhimurium and Typhi (species that are normally encountered in the environment) are the causative agents of gastroenteritis and typhoid fever, respectively.

Depending on the serotype of Salmonella strain and several host organism factors, the infecting bacteria may colonise solely the intestinal epithelium which would lead to gastroenteritis or it may spread beyond the gut (to the liver and spleen predominantly, causing typhoid fever).
Salmonella Typhimurium infection in humans is usually restricted to the digestive tract, with the exception of infants, the elderly or immunocompromised individuals (such as transplant patients or HIV infected individuals) in whom it can spread.
Salmonella Typhi on the other hand causes typhoid fever in humans while it is not pathogenic to animals. Interestingly, serotypes that lack host specificity, such as Salmonella Typhimurium, are more frequently associated with disease in young rather than in adult animals. This would suggest that the Typhimurium strain of bacteria has been unable to adapt to the mature immune system.

To understand the genetic engineering that underpins the attenuated variants of this bacteria, it is important to know some of the genes, their functions, and how they are regulated which I will briefly describe in the section below.

Approximately 90% of the genes found in the Salmonella Typhi strain are identical to the Salmonella Typhimurium serovar (the two strains that have served as the starting point for therapeutic attenuated strains). However, of the 4000 genes that these bacteria share some 200 genes in the Typhi strain are non-functional or have been inactivated, while most of these genes are fully functioning in the Typhimurium strain (genes that are similar and that are found in another species are called homologs).

Many of these aforementioned non-functional homologs are genes that govern virulence factors (which are genes that make a micro-organism (e.g.bacteria) more pathogenic). Most of these virulence factors are contained in clusters on the Salmonella genome. These clusters are called Salmonella Pathogenicity Islands (SPI). The Salmonella Typhimurium and Typhi strain genome share 11 SPIs. However they each also express virulence genes from specific SPIs unique to each strain., SPI14 in the case of the Typhimurium strain and SPI7, SPI15, SPI17, and SPI18 in the case of the Typhi strain.

Some of these virulence genes that are expressed by Salmonella govern its ability to multiply inside a range of cells such as epithelial cells (skin cells), macrophages, dendritic cells, and neutrophils (i.e. cells of the immune system). In order for Salmonella to get inside these host cells and survive a relatively hostile environment, it utilises two “Type III Secretion Systems” (otherwise known as T3SS). These T3SS consist of a number of proteins and form a structure on the outside of the bacterial wall that can be thought of as a needle. The SPIs that contain the genes (genes are essentially the “blueprint”) for the building blocks of this T3SS structure are SPI1 and SPI2. The genes contained on these SPIs include InvG, InvJ, PrgH, PrgI, PrgK, SpaO, SipB, SipC and SipD.

Invasion and intracellular survival is regulated by a number of different systems, including PhoQ/PhoP, and OmpR-EnvZ, while maturation of the Salmonella Containing Vacuole (SCV) is regulated by genes found on the SPI2 (to avoid phagosome-lysosomefusion and degradation).

These regulatory events (T3SS1 and T3SS2 modulation) happen within a timeframe of hours (0-4 hours) upon entering the cell (see figure 1 near the top in this blog post).

Why are there different cancer fighting Salmonella strains?
As mentioned above, attenuation of virulence factors is a key step in the process of creating Salmonella strains that can be utilised in a clinical setting. Approximately fifty Salmonella genes have been identified that can be modified and allow for the creation of viable attenuated strains with altered virulence and metabolic functions.
There are several techniques to generate strains with altered genetics. This includes the most basic technique of passaging Salmonella through selective media (after which you screen for surviving “mutants”), and more modern techniques like site-directed mutagenesis (precise and targeted molecular laboratory methods).

Targeting genes that regulate virulence is the most straightforward choice of modification. This involves inactivation of genes that encode for proteins which facilitate interaction with the host organism (human) or modification of factors (e.g. transcription factors) that regulate the expression of those genes. Examples of such genes includes phoP, phoQ (these regulate the expression of many genes that confer resistance to antimicrobial peptides), or the htrF gene which facilitates survival under conditions of stress.

Also, genes that encode for proteins involved in the metabolic pathway can be inactivated which subsequently results in strains that are dependent on external sources for compounds or nutrients (auxotrophic strains). An example of such a strain is the aro mutant or the pur mutant.

Please consult the table next to this section for a brief summary of other mutations found in attenuated Salmonella strains that may be used as a cancer therapy.

What scientific and clinical evidence exists for the efficacy of Salmonella therapy?
In this section I will highlight some interesting examples of research that has been conducted with various attenuated strains of Salmonella including some background on how scientists created them.

The first example relates to the auxotrophic strain A1-R (see table with list of strains above). A1-R was developed and created by Zhao and colleagues in Robert Hoffmann’s research group by modifying the parental strain (ATCC 14028). This particular strain is a Green Fluorescent Protein (GFP) expressing bacteria, a feature they used to their advantage during the tumour targeting optimisation process in mice. They essentially injected the intermediate strain (called A1) into H-29 human colon adenocarcinoma bearing mice and subsequently isolated GFP expressing bacteria from these tumours. In vitro experiments demonstrated that this newly isolated strain (called A1-R) had an increased affinity for these cancer cells (which was approximately six times stronger than the original strain).

This A1-R strain was subsequently tested in a range of human tumours that had been grafted onto nude mice. Types of cancers that were investigated include tumours of the breast, prostate, pancreas, and lung. These studies all resulted in significant tumour growth inhibition and in some cases even resulted in complete eradication of the cancer. For detailed scientific reports on these studies please consult the folowing publications: Kimura et al., 2010, Zhang et al., 2012, Hayashi et al., 2009, Hayashi et al., 2009.
Interestingly Hayashi and colleagues utilised the A1-R strain in a metastatic cancer of the pancreas (tested in mice bearing metastasised human pancreatic tumours). In five of six mice this metastasised cancer in the lymphnodes was eradicated within 7-21 days following intravenous injection of A1-R, while mice in the control group (the ones that did not get an injection with A1-R) suffered from increased levels of metastases.

Given that attenuated Salmonella strains have a natural preference for colonising tumours rather than normal host tissues (we are talking about orders of magnitude difference here), and that without any further modifications they inhibit tumour growth, some researchers have used such strains to exert tumour directed cytotoxic effects by inducing the immune system in order to mount an immune response against the tumour.

Also, as mentioned before, less than optimal tumour targeting, and level of toxicity associated with current standard cancer therapies makes Salmonella based therapies a serious alternative. What's more, solid tumours harbour hypoxic regions that are often resistant to many forms of therapy (including radiation and other treatments). As such a recently developed facultative anaerobic strain by Yu and colleagues at the Huang lab may well offer a potential solution to this major issue in cancer therapy. In their relatively recently published work they show that in breast tumour bearing mice, their YB1 strain targeted the tumour and inhibited its growth considerably. Importantly, this particular strain was rapidly eliminated from normal tissues and blood (3 days post infection Salmonella was barely detectable in the liver). This would suggest that YB1 is a safe bacterial vector for anti-tumour therapies without the trade-off of reduced tumour fitness (which has often been the case with other attenuated Salmonella strains (compared to the parental strain)).

These researchers used a recombineering approach to create a Salmonella strain that is not viable in normal tissues by placing an essential gene, asd, under the control of a hypoxia-induced promoter (the FNR binding site containing pepT promoter (PpepT) was used to drive expression of asd, while an antisense promoter of the sodA gene, which is negatively regulated by FNR, was added to the PpepT-asd construct to make the strain YB1 (the sodA gene promoter was added to the construct to prevent leakage from the pepT promoter)). The asd gene encodes an enzyme that is essential for the synthesis of DAP (a fundamental component of the bacterial cell wall). As a result this Salmonella species only expresses asd in hypoxic conditions and as such it grows well under hypoxia, but will lyse under conditions experienced in normal tissue.

As bacteria are expected to induce a host immune response, the scientists observed that neutrophils were found in the YB1 infected tumours. This would suggest YB1 may enhance tumour killing by strongly attracting neutrophils to the tumour.
However, it is important to note that YB1 did not completely inhibit breast tumour growth.

Nevertheless, in subsequent experiments they compared the widely used anti-cancer 5-FU with YB1 and their effects on tumour growth respectively.
YB1 retarded tumour growth with an effectiveness greater than that of the drug 5-FU alone. When the investigators combined YB1 and 5-FU treatment they showed a synergistic effect where tumour growth was almost brought to a complete standstill (see graph in Figure 1 at the top of this article)

In summary, YB1-like bacteria could have the advantages of an obligate anaerobic bacterium (in tumour targeting) while maintaining the chemotaxic properties and ability to target metastasis.

As such the recombineered ‘‘obligate’’ anaerobe, YB1, represents a new direction in producing bacterial therapeutic agents for cancer.

Graph copied from Yu et al., 2012 which demonstrates
remarkable tumour growth inhibition as a combination therapy
with 5FU

List of attenuated Salmonella strains used in cancer therapies, including info on the genes that
have been modified.

Where can you get access to Salmonella immunotherapy for cancer?
Unfortunately, you can only get access to this therapy via clinical trials. This type of therapy is not yet approved.
Currently the following clinical trials are still recruiting patients for their studies:

There are currently no ongoing studies in the USA (see the clinical trial data base for the USA)
In the EU (Europe) one clinical trial is currently being conducted:

A pilot phase II study of a combined immunotherapy protocol based on oral vaccination and direct intratumoral injection of Salmonella Typhi Ty21a Vivotif in metastatic cutaneous melanoma patients. The medical condition of interest is Metastatic stage III and IV M1a melanoma. This study is managed by the Istituto Europeo di Oncologia in Milan, Italy (see the clinical trial data base for the EU).

Please keep in mind that there are several physicians / oncologists that want to conduct clinical trials with this type of therapy. So please check the databases regularly for updates. If you are a medical doctor and would like to conduct a clinical trial investigating attenuated Salmonella, please get in touch.

Also, if you are a physician or sponsor and are conducting a clinical trial in which Salmonella is used to treat cancer, then please contact me if you would like to have your trial listed on this page.

New developments in Salmonella based Immunotherapies?
Given the intracellular lifestyle and immunomodulatory properties associated with attenuated Salmonella strains, they are also well suited to deliver therapeutic molecules right into the cancer cells.
There are a range of cargo molecules, but all are based on inserting genetic material which codes for proteins such as tumour antigens (e.g. HSPPC-96), cytokines (e.g. IL-18), apoptosis-inducing factors (e.g. TRAIL), prodrug-converting enzymes, or genetic material that encodes for short hairpin RNAs (shRNAs) which are able to silence expression of a gene of choice (e.g. a gene such as ERBB2 or EGFR that is normally upregulated in cancer).

In addition, recent reports indicate that Salmonella Drug Conjugates (SDCs) may soon become reality and potentially common place in the treatment of diseases such as cancer. Park and colleagues, from the Chonnam National University in South Korea, developed this SDC they dubbed “bacteriobot” which in simple terms is an attenuated salmonella strain covalently linked to a robotic device, 3 micrometers in size, that automatically sprays anticancer drugs when it reaches a cancer cell. The creation has already been patented in dozens of countries, including the United States, Japan and all members of the European Union.

In summary, bacterial cancer therapy based on various Salmonella strains is supported by solid preclinical and early phase clinical data.

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Old 19-06-2014, 02:59 AM   #610
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CRS-207 is based on Aduro’s Listeria platform and has been engineered to express the tumor-associated antigen mesothelin. Aduro's lead program is the combination of CRS-207 and GVAX Pancreas in patients with metastatic pancreatic cancer. For more information, please see Clinical Trials.

Aduro is also evaluating CRS-207 in combination with chemotherapy in patients with mesothelioma. For more information, please see Clinical Trials.

ADU-623 is Aduro's first clinical bivalent Listeria-based immunotherapy. Aduro collaborators are evaluating ADU-623 in an investigator-sponsored Phase 1 clinical trial in patients with glioblastoma. For more information, please see the listing on clinicaltrials.gov.

ADU-214 is a bivalent Listeria-based immunotherapy that targets both mesothelin and an EGFR mutation known to be common in several diverse solid tumor malignancies.

Aduro is working with collaborators to design and fund a Phase 1 trial in ovarian cancer. In addition, Aduro is working with collaborators to design and fund a Phase 1b trial to evaluate the combination of ADU-214 and radiation in patients with non-small-cell lung cancer.

In May 2014, Aduro entered into an agreement granting Janssen Biotech, Inc. an exclusive, worldwide license to certain product candidates specifically engineered for the treatment of prostate cancer based on its novel LADD immunotherapy platform. For more information, please read the press release.

In addition, Aduro has received a Congressionally Directed Medical Research Programs (CDMRP) grant from the Department of Defense to complete the preclinical development of a novel, Listeria-based immunotherapy for prostate cancer. For more information, please read the press release.

CDNs are small molecules that signal through STING and induce a potent immune response. The first clinical indication has not yet been determined. The first clinical trial may evaluate CDNs in combination with antibody-dependent cell-mediated cytotoxicity (ADCC), chemotherapy and/or radiation. For more information, please see cyclic dinucleotides.

STINGVAX is the combination of CDNs and GVAX.

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Old 19-06-2014, 05:06 AM   #611
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Technology Overview
Aduro has three technology platforms designed to activate potent and lasting immune responses against cancer:
Live, attenuated Listeria monocytogenes strains are potent activators of immune responses and have been genetically engineered for safety and to efficiently express proteins found on tumors.
GVAX is a family of immunotherapies derived from human cancer cell lines that have been genetically engineered to recruit the immune system.
Proprietary cyclic dinucleotides (CDNs) are small-molecule adjuvants that target an important receptor known as STING (STimulator of INterferon Genes) and simultaneously activate several important immune response pathways.

Live, attenuated, double-deleted Listeria monocytogenes (LADD): For more than 50 years, immunologists have used Listeria as a research tool to study the mammalian immune system, and now Aduro is engineering Listeria to treat cancer. The platform has shown to be well tolerated in multiple clinical trials.

Listeria has multiple advantages as an immunotherapy platform:
Listeria signals to the innate immune system through multiple pathways, activating cell surface Toll-like receptors and intracellular Nod-like receptors.
It directly targets dendritic cells, one of the most important types of cells in initiating an immune response.
After being taken up by dendritic cells, Listeria delivers the disease antigen(s) into the cytosol where they are processed by the host cellular machinery and presented to the immune system.
Unlike other vectors that can be neutralized by antibodies, Listeria can be repeatedly administered.
Listeria is exceptional at boosting the efficacy of other vaccines/treatments.
Listeria is easy to manufacture.

GVAX is portfolio of irradiated tumor cell lines that have been engineered to recruit immune cells by expressing GM-CSF, the most potent immune cell recruitment factor. GVAX vaccines are well suited for combination therapy because (a) they present numerous antigens to the immune system, thereby enabling a broad-based immune response and (b) have a well-established, favorable safety profile demonstrated in multiple clinical trials.

The combination of GVAX Pancreas and the immune checkpoint inhibitor ipilimumab (Yervoy® from Bristol-Myers Squibb) was more effective than ipilimumab alone in a 30 patient study: mOS was 3.6 vs. 5.7 months (p=0.072; HR=0.51) (J Immunother. 36(7), 382-389). In a study of GVAX Prostate and ipilimumab in 28 patients with metastatic castration-resistant prostate cancer, 50% or greater declines in prostate-specific antigen (PSA) were seen from baseline in seven patients (25%) (Lancet Oncol. 13(5), 509-517).

In addition, Aduro has demonstrated that co-formulation of CDNs with GVAX, termed STINGVAX, results in superior anti-tumor efficacy in pre-clinical cancer models compared to GVAX alone.

Cyclic Dinucleotides
Cyclic Dinucleotides (CDNs). The STING signaling pathway has recently been identified as an important cellular pathway that is triggered in response to a viral or bacterial infection. Specifically, STING is activated by cyclic dinucleotides (CDNs), which may be produced by bacteria or produced by antigen presenting cells in response to sensing cytosolic DNA. Unmodified CDNs have been shown to induce type I interferon and other co-regulated genes, which in turn facilitate the development of a specific immune response.

Aduro has modified the naturally-occurring CDNs to achieve certain improved characteristics that are believed to be important for therapeutic development. As shown in vitro, the derivatives are resistant to digestion with phosphodiesterase, they are able to activate the intracellular STING receptor in the absence of cell permeabilization and they induce a higher level of stimulation of human peripheral blood mononuclear cells (PBMCs). As shown in in vivo animal models, they induce a higher magnitude of peak and memory antigen-specific CD4 and CD8 T cell responses and they significantly inhibit tumor growth, which correlates with increased survival.

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Old 20-06-2014, 08:02 AM   #612
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Old 20-06-2014, 08:16 AM   #613
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AFTVac therpay is easy and possible in out-patient basis

(1) Injections

Intrdermal injections will be carried out a total of 5 times, i.e., DTH-1 (delayed-type hypersensitivity test-1, 0.1 ml), AFTVac inoculation-1 (0.2 ml x 5 sites), -2, -3, and finally DTH-2 (delayed-type hypersensitivity test-2).

(2) Schedule

Clinical Trial (Liver Cancer)


Phase I/IIa clinical trial

High rate of recurrence has been well known even after curative resection of hepatocellular carcinoma (HCC, the most frequent liver cancer). Recurrence control is the primary goal of novel HCC treatments.

To observe prophylactic effect of AFTVac on HCC recurrence, patients were enrolled if they were having histologically confirmed HCC (mono-centric HCC stage II or lower) and adequate hepatic function (Child-Pugh A and B).

Further inclusion criteria were age 18-80 and no systemic chemo-, radio-, or immuno-therapy within 1 month prior to the vaccination. They were enrolled with written informed consent.

The patients were treated in three cohorts, containing at least 3 patients each. We gave increasing doses of the vaccine. Recurrence of HCC was detected by imaging techniques (ultrasonography and CT-scan) and confirmed by pathological inspection after needle biopsy or secondary resection.

REF: Peng, B. G., Liu, S. Q., Kuang, M., He, Q., Totsuka, S., Huang, L., Huang, J., Lu, M-D., Liang, L-J., Leong, K. W., and Ohno, T.*: Autologous fixed tumor vaccine: A formulation with cytokine-microparticles for protective immunity against recurrence of human hepatocellular carcinoma. Jpn. J. Cancer Res. 93: 363-8, 2002. (*Corresponding author)

Fig. 1

For dose-1, -2 and -4 tests (there is no dose-3 because we approximately doubled and quadrupled contents of the vaccine components), all patients (3 per group) tolerated the vaccination well. We observed no adverse effect in the patients except patient-3 (dose-1) and patient-8 (dose-4), both of whom showed dry desquamation and pruritus (Grade II) at the injection site 2 weeks after the second and first vaccine injection, respectively. These weak adverse effects disappeared after 2 weeks.

In the follow-up observation, two of DTH-response-negative patients in the dose-2 group revealed the first recurrence 9 and 10 months after the curative resection. However, we observed no HCC recurrence in any of the other patients when the majority of the patients passed through one year after the resection (Red line).

We compared these HCC recurrences with those of historical control patients (Blue line). To avoid potential bias influenced by technology in the curative resection of HCC, we restricted historical control patients, as the vaccinated patients, to those operated in the same department, with histologically-confirmed mono-centric HCC, and born closest to the period preceding the present clinical trial with no further treatment before the time of HCC recurrence.

After applying strictly the same eligibility and exclusion criteria of the Phase I/IIa patients, we enrolled 24 patients in the historical control group. No essential difference was observed between the 12 vaccinated patients and the 24 historical control patients in the base-line data except that contents of HBV-positive patients are mismatched, i. e., the former and the latter included 10 (83%) and 14 (58%), respectively.

The two groups revealed statistically significant difference (log-rank test, P<0.05).

The recurrence in these historical control patients was consistent with the observation of Lai, et al. 1 year after the operation (Lai, E. C., et al. Hepatic resection for hepatocellular carcinoma. An audit of 343 patients. Ann. Surg ., 221: 291-298, 1995).

So far as we have observed for more than a year, no adverse effect was found in the hepatic function of the vaccinated patients. Vaccination-related impairment of other vital organ (i.e., kidney and bone marrow) functions was not found. Occurrence of autoimmune disease was not observed.

Phase IIb clinical trial with randomized control patients

We have conducted a phase II clinical trial with randomized control patients to determine if the AFTVac protects against post-surgical recurrence of hepatocellular carcinoma (HCC).

REF: Kuang, M., Peng, B. G., Lu, M. D., Liang, L. J., Huang, J. F., He, Q., Hua, Y. P., Totsuka, S., Liu, S. Q., Leong, K. W. and Ohno, T.*: Phase II Randomized Trial of Autologous Formalin-Fixed Tumor Vaccine for Postsurgical Recurrence of Hepatocellular Carcinoma. Clin. Cancer Res. 10: 1574-1579, 2004. (*Corresponding author)

Fig. 2 Randomization of HCC patients for the Phase IIb clinical trial

Multivariate analysis revealed that the vaccine group remained unchanged compared with the control group.

In a median follow-up of 15 months, the risk of recurrence in vaccinated patients was reduced by 81% [95% confidence interval (CI), 33-95, P = 0.003]. Vaccination significantly prolonged the time to first recurrence, and improved the recurrence-free survival and overall survival rates.

Fig. 3 Recurrence-free survival (P = 0.003)

Fig. 4 Overall survival (P = 0.01)

There was a significant interaction between recurrence after vaccination and tumor size ( P = 0.0004), but the effect was clinically important because all recurrences in the vaccine group were observed in patients with tumors >= 50 mm in size (3/9, 33%), whereas the recurrences in the control patients with tumors >= 50 mm in size were 10/11, 91% (P=0.003).

The survival rate of vaccinated patients with tumors <50 mm in size, TNM stage I/II or negative invasive histology was 100% (0/9, 0/11 and 0/12, respectively), compared with 20% (2/10), 23% (3/13) or 31% (4/13) in the control group. Overall survival in patients with tumors >= 50 mm in size was also significantly improved (P = 0.04). At the end of the follow-up, the mortality rate was 6% (1/18) in the vaccine group and 38% (8/21) in the control group.

AFTVac for glioblastoma multiforme (GBM), a pilot study

We performed a pilot study to investigate the safety and feasibility of autologous formalin-fixed tumor vaccine (ATFVac) and the clinical responses in glioblastoma multiforme (GBM) patients. GBM (WHO grade IV) is the worst hard-to-treat malignant brain tumor.

Of the 12 patients, 8 had recurrent disease while 4 had been treated with regular radiation and chemotherapy but retained a visible tumor mass.

One showed a complete response, one showed a partial response, two showed minor responses, one had stable disease, and seven exhibited progressive disease.

The median overall survival period was 24 months from the primary resection, 10.7 months from the initiation of the AFTVac treatment but 3 of the 4 responders survived for 20 months or more after AFTVac inoculation.

The AFTVac therapy is safe and feasible, and could significantly improve the outcome of GBM.

REF: Ishikawa, E., Tsuboi, K.*, Yamamoto,. T., Muroi, A., Enomoto, T., Takano, S., Matsumura, A., Ohno, T., A clinical trial of autologous formalin-fixed tumor vaccine for glioblastoma multiforme patients. Cancer Sci., 98(8): 1226-1233, 2007. (*Corresponding author)

Fig. 1

Overall survival from the primary resection
(GBM patients)

Fig. 2

Overall survival from the AFTVac inoculation
(GBM patients)

Glioblastoma multiforme (GBM) is currently treated with a combination of surgical removal, external beam radiotherapy, and nitrosourea chemotherapy. However, it is not overstating the case to say that GBM patients are never completely cured since most quickly suffer relapses and over 90% succumb within 5 years of diagnosis (1). Improving the outcome of GBM and extending the life span of GBM patients is thus a matter of great concern to clinicians.

With regard to current GBM therapies, it has been suggested that cytoreductive surgery may be beneficial (2, 3). However, others failed to detect significant differences in the survival of cases who had been subjected to different surgical modalities (4, 5). This has been attributed to the extreme diffuseness with which the tumor invades the brain parenchyma. In contrast, conventional x-ray radiotherapy at a dose of approximately 60 Gy has been found to be significantly beneficial, as it extends the median survival time by 18 weeks (6) or 5.6 months (7). In addition, a large-scale meta-analysis of the therapeutic effects of chemotherapy indicate that it extends survival by 2 months (8). Indeed, temozolomide chemotherapy was found to extend survival by only 2.5 months, resulting in the overall survival, 14.5 months after the primary resection (9).

The current inability to cure GBM has led to the development of various novel GBM therapies. In particular, there is growing interest in treatments that involve tumor-specific immune reactions because such treatments potentially have a high benefit-to-risk ratio. Moreover, these treatments may be useful in preventing tumor recurrence after initial localized treatments that involve surgery and radiotherapy. Indeed, our preliminary clinical studies have revealed that immunotherapeutic treatment of recurrent malignant glioma patients with ex vivo-expanded autologous tumor-specific T lymphocytes yields favorable results (10, 11).

However, this therapeutic approach suffers from a serious limitation, namely, the successful ex vivo-expansion of autologous tumor-specific T lymphocytes requires sufficient numbers of live tumor cells. This in turn necessitates the expansion of primary cultured tumor cells and the establishment of tumor cell lines (10, 11). These processes are generally time-consuming and tedious; moreover, tumor cells cannot always be successfully subcultured (12).

An alternative immunotherapeutic approach is to employ the formalin-fixed paraffin-embedded blocks of tumor tissues that are routinely prepared and stored after surgical removal.

Since formalin fixation preserves the specific antigenicity of tumor cells (13, 14, 15), these preparations could serve as an alternative tumor antigen source for cytotoxic T lymphocyte s (CTL) induction. Indeed, we have demonstrated that tumor-specific autologous CTLs can be generated by using several fixed sections; these cells have comparable activity and specificity to those induced by continuously cultured live tumor cells (14, 15).

Moreover, it has been shown that HLA-A2402-restricted carcinoembryonic antigen (CEA)-specific CTLs can be induced by culturing human peripheral blood mononuclear cells (PBMCs) with formalin-fixed (but not paraffin-embedded) autologous adhesive PBMCs loaded with CEA protein-bound latex-beads (16). Such CTLs could also be generated by using formalin-fixed adherent cells pulsed with 9- or 10-mer CEA-derived MHC-class I-presented tumor-associated antigens (TAA) (16).

The latter report further supports the notion that peptide TAAs derived from fixed cells or proteins are formalin-resistant. Thus, formalin-fixed and/or paraffin-embedded tumor cells/tissues may be useful TAA sources that can be employed to generate effective anti-tumor immune cells, as our laboratory has shown a case whose CTL were induced ex vivo on the formalin-fixed autologous GBM cells (see the case no. 1 in ref. 11).

Based on these observations, we previously constructed autologous formalin-fixed tumor vaccine (AFTVac) from surgically extirpated tumor tissues (12, 13) and showed that these vaccines had a positive immunotherapeutic effect when tested with an experimental rat brain tumor model (17). In addition, retrospective (13) and prospective randomized clinical trials (18) have revealed AFTVac is efficacious in patients with hepatocellular carcinoma.

We recommend that, after the primary resection of the GBM, the patients should be treated with local radiation (60Gy), and then AFTVac (but not the standard chemotherapy, Temodar, before the AFTVac inoculation) for efficient induction of cytotoxic T lymphocytes in vivo. Chemotherapy may strongly inhibit these cellular immune responses.

If the patient had recurrence after the AFTVac, then treat the patient with the standard chemotherapy, Temodar, with frequent monitoring of peripheral blood lymphocytes. Hopefully, keep the lymphocyte level over 1000/uL to maintain potential cellular immune responses such as those with natural killer cells.

Note that, once lymphopenia was induced by Temodar, full recovery of the lymphocyte number requires 5 months (median value) after stopping Temodar (Su, Y.B., et al., Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications. J Clin Oncol. 22(4):610-616, 2004).

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Old 21-06-2014, 05:20 AM   #614
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New Oral Angiogenesis Inhibitor Offers Potential Nontoxic Therapy For A Wide Range Of Cancers

The first oral, broad-spectrum angiogenesis inhibitor, specially formulated through nanotechnology, shows promising anticancer results in mice, report researchers from Children's Hospital Boston.

A Lodamin nanoparticle with TNP-470 (the drug's active ingredient) at the core, protected by two short polymers (PEG and PLA) that allow TNP-470 to be absorbed intact when taken orally. Once the nanoparticles (known as polymeric micelles) reach the tumor, they react with water and break down, slowly releasing the drug. Lodamin appears to retain TNP-470's potency and broad spectrum of anti-angiogenic activity, but with no detectable neurotoxicity and greatly enhanced oral availability.

The first oral, broad-spectrum angiogenesis inhibitor, specially formulated through nanotechnology, shows promising anticancer results in mice, report researchers from Children’s Hospital Boston.

Findings were published online on June 29 by the journal Nature Biotechnology.

Because it is nontoxic and can be taken orally, the drug, called Lodamin, may be useful as a preventive therapy for patients at high risk for cancer or as a chronic maintenance therapy for a variety of cancers, preventing tumors from forming or recurring by blocking the growth of blood vessels to feed them. Lodamin may also be useful in other diseases that involve aberrant blood-vessel growth, such as age-related macular degeneration and arthritis.

Developed by Ofra Benny, PhD, in the Children’s laboratory of the late Judah Folkman, MD, Lodamin is a novel slow-release reformulation of TNP-470, a drug developed nearly two decades ago by Donald Ingber, MD, PhD, then a fellow in Folkman’s lab, and one of the first angiogenesis inhibitors to undergo clinical testing. In clinical trials, TNP-470 suppressed a surprisingly wide range of cancers, including metastatic cancers, and produced a few complete remissions. Trials were suspended in the 1990s because of neurologic side effects that occasionally occurred at high doses, but it remains one of the broadest-spectrum angiogenesis inhibitors known.

Lodamin appears to retain TNP-470’s potency and broad spectrum of activity, but with no detectable neurotoxicity and greatly enhanced oral availability. While a number of angiogenesis inhibitors, such as Avastin, are now commercially available, most target only single angiogenic factors, such as VEGF, and they are approved only for a small number of specific cancers. In contrast, Lodamin prevented capillary growth in response to every angiogenic stimulus tested. Moreover, in mouse models, Lodamin reduced liver metastases, a fatal complication of many cancers for which there is no good treatment.

“The success of TNP-470 in Phase I and II clinical trials opened up anti-angiogenesis as an entirely new modality of cancer therapy, along with conventional chemotherapy, radiotherapy and surgical approaches,” says Ingber, now co-interim director of the Vascular Biology Program at Children’s.

TNP-470 was first reformulated several years ago by Ronit Satchi-Fainaro, PhD, a postdoctoral fellow in Folkman’s lab, who attached a large polymer to prevent it from crossing the blood-brain barrier (Cancer Cell, March 2005). That formulation, Caplostatin, has no neurotoxicity and is being developed for clinical trials. However, it must be given intravenously.

Benny took another approach, attaching two short polymers (PEG and PLA) to TNP-470. Experimenting with polymers of different lengths, she found a combination that formed stable, “pom-pom”-shaped nanoparticles known as polymeric micelles, with TNP-470 at the core. The polymers (both FDA-approved and widely used commercially) protect TNP-470 from the stomach’s acidic environment, allowing it to be absorbed intact when taken orally. The micelles reach the tumor, react with water and break down, slowly releasing the drug.

Tested in mice, Lodamin had a significantly increased half-life, selectively accumulated in tumor tissue, blocked angiogenesis, and significantly inhibited primary tumor growth in mouse models of melanoma and lung cancer, with no apparent side effects when used at effective doses. Subsequent tests suggest that Lodamin retains TNP-470’s unusually broad spectrum of activity. “I had never expected such a strong effect on these aggressive tumor models,” Benny says.

Notably, Lodamin accumulated in the liver without causing toxicity, preventing liver metastases and prolonging survival. “This was one of the most surprising things I saw,” says Benny. “When I looked at the livers of the mice, the treated group was almost clean. In the control group you couldn’t recognize the livers -- they were a mass of tumors.”

TNP-470 itself has an interesting history. It was derived from fumagillin, a mold with strong anti-angiogenic effects that Ingber discovered accidentally while culturing endothelial cells (the cells that line blood vessels). Ingber noticed that in certain dishes -- those contaminated with the mold -- the cells changed their shape by rounding, a behavior that inhibits capillary cell growth. Ingber cultured the fungus, disregarding lab policy, which called for contaminated culture to be discarded immediately. He and Folkman later developed TNP-470, a synthetic analog of fumagillin, with the help of Takeda Chemical Industries in Japan (Nature, December 1990). It has shown activity against dozens of tumor types, though its mechanism of action is only partly known.

“It’s been an evolution,” says Benny, “from fumagillin to TNP-470 to Caplostatin to Lodamin.”

Lodamin and Caplostatin have been optioned for clinical development by SynDevRx, Inc., a Cambridge, Mass.-based biotechnology company. Benny, who is from Israel, coined the name Lodamin from Hebrew. (“Lo dam” means “no blood.”) She continues to study Lodamin’s effects in other animal models of cancer, and in macular degeneration with Robert D’Amato, MD, PhD, in the Vascular Biology program.

Folkman, the Lodamin paper’s senior author, died unexpectedly in January, just days after Benny submitted the paper for publication. The paper, a part of his legacy, is dedicated to his memory.

The study was supported in part by the U.S. Department of Defense.

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Old 21-06-2014, 01:21 PM   #615
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Old 25-06-2014, 03:28 AM   #616
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Personalized T cell immunotherapy that can target and kill tumor cells, regardless of tumor origin, disease stage, and prior treatments.

The eACT™ platform is the foundation for Kite Pharma’s lead programs in collaboration with the National Cancer Institute (NCI), which is advancing multiple clinical trials in patients with hematological and solid tumors. In this novel approach, a patient's peripheral blood T cells are genetically modified ex vivo to express receptor molecules that render these T cells highly efficacious against cancer.

eACT™ involves the genetic engineering of T cells to express either chimeric antigen receptors (CAR) or T cell receptors (TCR). Both these categories of products encompass extracellular tumor antigen recognition domains and endogenous or engineered intracellular T cell activating domains. Together, these ensure a broad coverage across intracellular and membrane targets, solid tumors and hematological malignancies:

Contains a single chain antibody domain that binds to a cell surface tumor antigen, linked to intracellular T cell activating domains. CAR products recognize tumor antigens expressed on the cellular membrane.

Recognizes a tumor antigen epitope presented by the major histocompatibility complex (MHC) on the tumor cell along with T cell activating domains. TCR products recognize tumor antigens irrespective of their cellular localization.

The engineered T cells, when administered back to the patient, become activated upon engagement with the specific tumor antigen and selectively eradicate the targeted tumor cells.

Clinical studies of engineered T cells performed at the NCI have shown significant and durable objective clinical responses in cancer patients with advanced metastatic disease, including those with hematological (lymphoma and leukemia) and solid tumors (refractory melanoma, sarcoma). Kite has a Cooperative Research and Development Agreement (CRADA) with the NCI relating to Research and Development of CAR- and TCR-based product candidates for clinical testing. Kite holds the right to exclusive commercialization licenses from the National Institute of Health (NIH) related to the CRADA research plans.

Based on the promising clinical trial results, Kite Pharma is planning to advance its lead product candidate to a multicenter clinical trial in refractory diffuse large B cell lymphoma, with additional clinical filings anticipated in multiple B-cell malignancies. In addition, Kite Pharma is developing a diversified pipeline of CAR and TCR products with broad applicability across various tumor types.


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Old 25-06-2014, 09:30 AM   #617
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Granulocyte monocyte colony stimulating factor (GM-CSF), a cytokine critical for immune activation, and
CAIX, a hypoxia-induced protein that has been found to contribute to tumor cell survival and cancer progression. CAIX demonstrates highly increased expression in various primary and metastatic cancer types, yet displays limited expression in normal tissues.

A patient's DCs engineered with GM-CAIX are administered back to the patient in order to activate an immune response against CAIX-expressing tumor cells. Preclinical studies with DCs expressing GM-CAIX conducted in an in vivo model demonstrated significant growth inhibition of established CAIX-expressing kidney cancer tumors.

Kite Pharma’s DC-Ad GM-CAIX is currently undergoing an investigator-sponsored phase 1 clinical study at UCLA. This trial enrolls patients with clear cell RCC (ccRCC). CAIX is highly expressed in over 85% of patients with primary and metastatic ccRCC, and it is also genetically linked to the development of this disease. Despite the introduction of several new targeted therapies (which have shown toxicity with limited efficacy), ccRCC remains an unmet medical need accounting for over 13,000 annual deaths in the U.S.

Upon demonstration of safety and activity in ccRCC, Kite plans to evaluate GM-CAIX-based vaccine approach in various cancer indications.

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Old 25-06-2014, 09:46 AM   #618
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What is Cancer? Is there a cure in sight?

Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar.—Otto H. Warburg
The first common property of Cancer cells described was the Warburg effect, the dysregulated production of energy from sugar in the cancer cell. Normal cells go through the Krebs cycle to produce energy, cancer cells go through anaerobic glycolysis even in the presence of oxygen. The Warburg effect was described by the Jewish-German scientist Otto Heinrich Warburg in 1924. (http://www.sciencemag.org/content/32...9.figures-only)


Today, 95% of all tumors can be diagnosed based on the Warburg effect through PET/CT, a technique in which high metabolic activity on radiolabeled glucose is tracked by imaging and compared to simultaneous CT scan pictures.
With the discovery of DNA, advances in molecular biology, and the discovery of cancer viruses and the mutagenic properties of environmental or industrial carcinogens, attention shifted to the genetic profile of Cancer. Genetic mutations within genes called oncogenes were found to contribute to cancer development as part of a multi-step process we call carcinogenesis. Carcinogenesis also includes the inactivation of other genes, called tumor suppressors that resist the cancerous phenotype as part of their normal function. Carcinogenesis is thought to be initiated by genetically inherited mutations in oncogenes and tumor suppressors, epigenetics or chemical and environmental mutagens. Viruses may also be involved in this multistep process of carcinogenesis. During the process of Carcinogenesis cancer cells begin to undergo uncontrollable cell division and to lose their ability to comprehend growth inhibitory signals in their environment. In response to the same signals normal cells are prevented from growing uncontrollably and maintain a predetermined function and lifespan within the organ and tissue in which they are found.
Cancer cells growing uncontrollably, interfere with the normal organ function at the site where they appear. Cancers are often invasive, moving into tissues other than the one in which they originated, or they are metastatic, spreading from the site where they first appeared to other organs in the body usually by entering blood circulation or the lymphatic system. Cancers are staged according to their invasiveness (histological grade) and their metastatic properties (Stages I-IV). The more invasive and metastatic a Cancer, the higher its grade and stage, the harder it has been to control or eradicate and the poorer the prognosis for the patient.
Recent developments show a multitude of cancers cells independent of tissue of origin and oncogene/tumor suppressor or other genetic profiles to be susceptible to obliteration in vitro and in vivo by 3-bromopyruvate, PSL-001 (or Glycobloc). The fact that 95% of all Cancers are detectable based on their metabolic profile by PET/CT scans and can be killed by a single drug should alert us to re-thinking the current doctrine that Cancer is a multitude of diseases that will require a plethora of treatments. The fact of the matter is, when the cell cannot metabolize properly, all sorts of functional and genetic aberrations may arise.
Whether genetic alteration comes first or after the deregulation of cellular energy production is a question of the chicken and the egg. Such a question, however, may still be relevant in our understanding of genetic cancer risk factors.
In the words of James Watson, Nobel Laureate and the co-discoverer of the DNA’s helical structure, as a result of the work on 3-bromopyruvate: “We must focus much, much more on the wide range of metabolic and oxidative vulnerabilities that arise as consequences of the uncontrolled growth and proliferation capacities of cancer cells.“
Hexokinase 2, a cytosolic protein in most normal cells, is over-expressed in cancer cells and is found bound to their mitochondrial membrane. Hexokinase2 plays an initiating role in the high glycolytic activity of the Cancer Cell. 3-bromopyruvate was identified as a candidate for Hexokinase 2 inhibition.

In March 2008, Lewis Cantley’s laboratory at Harvard Medical School announced they had identified another enzyme that gave rise to the Warburg effect, as PKM2 kinase a form of the Pyruvate Kinase, found in all of the cancer cells they had tested but not usually found in healthy tissue. When PKM2 was switched off in the cancer cells, they lost their ability to grow. PKM2 is up-regulated in processes like hematopoesis or would healing that require rapid growth and induce cell division.

In 2013, scientists from the Whitehead institute showed that cancer cells either selectively uptake 3-bromopyruvate or can be induced to selectively uptake 3-bromopyruvate by pre-treatment with butyrate (a substance available as a food supplement).

Glycolysis in cancer cells, during the Warburg effect, creates an acid tumor environment. In January 2014, Scientists at Harvard and Tokyo was found showed that a low-pH environment can reprogram normal, somatic cells to acquire properties of less differentiated progenitor stem cells.
In conclusion, these fundamental discoveries are sending us full circle back to where we started our efforts on Cancer research in 1924 with Otto Warburg and command a rethinking of our current understanding.
Today two more drugs based on the metabolic effects of cancer cells are being tested, DCA and 2-deoxyglucose. Both of these drugs were available as pharmaceuticals for diseases other than Cancer and clinical trials could be initiated on them despite the tremendous difference in their experimental efficiencies when compared to 3-bromopyruvate. 3-bromopyruvate is now also, an orphan drug fast-tracked by the FDA for clinical trials for the treatment of liver cancer. The world is holding its breath. What has been shown to be a cure of lung, breast, liver and blood cancers in animal systems and a cure for humans on a humanitarian basis, will soon be tested on a wider basis.
Cancer is a metabolic disease, marked by genetic instability, on which the American people proclaimed a war in 1974, when 1 in 16 Americans would be diagnosed with Cancer and die from it. Today, 1 in2 men and 1 in 3 women will be diagnosed with Cancer and will eventually succumb to the disease. Despite the availability of better diagnostics and successful treatment of many leukemias and lymphomas, the Dana Farber reports that rates in Cancer deaths have been reduced by 1.2 per cent in the last ten years, mainly due to the reduction of smoking in the population. Under any logical examination, free of denial, the numbers are dire. Luckily, decades of scientific research are finally producing a practical handle on our understanding of cancer’s vulnerabililities and a cure, based on scientific principle, is in sight.


For the Warburg effect, Cancer and 3-bromopyruvate:


Articles and announcements:
1. From the quarterly of the AACR: http://www.cancertodaymag.org/Winter...ne.aspx?Page=1
2. http://www.presciencelabs.com/cancer...evelopment.php
3. http://www.marketwatch.com/story/pre...rug-2013-07-24
4. War on cancer: 3BP and the metabolic approach to cancer: a visit with Peter Pedersen and Young Hee Ko. http://www.thefreelibrary.com/War+on.....-a0332893717
5. From the Whitehead Institute at MIT: Cell surface transporters exploited for cancer drug delivery http://wi.mit.edu/news/archive/2012/...-drug-delivery

Worthy Quote
To quote James Watson, of Cold Spring Harbor Laboratory co-discoverer of the DNA’s double helix structure and Nobel Laureate:
“We must focus much, much more on the wide range of metabolic and oxidative vulnerabilities that arise as consequences of the uncontrolled growth and proliferation capacities of cancer cells.
As human cancers become driven to more aggressive glycolytic states, their ever-increasing metabolic stress makes them especially vulnerable to sudden lowering of their vital ATP energy supplies. 3-Bromopyruvate, the powerful dual inhibitor of hexokinase as well as oxidative phosphorylation, kills highly dangerous hepatocellular carcinoma cells more than 10 times faster than the more resilient normal liver cells and so has the capacity to truly cure, at least in rats, an otherwise highly incurable cancer“ http://rsob.royalsocietypublishing.o...full#corresp-1

Scientific papers on Glycobloc (3-bromopyruvate) from Johns Hopkins alone (there are many other researchers around the world working on it)

1. Advanced cancers: eradication in all cases using 3-bromopyruvate
therapy to deplete ATPq. Young H. Koa, Barbara L. Smith, Yuchuan Wang, Martin G. Pompera, David A. Rinic, Michael S. Torbensond, Joanne Hullihenb, Peter L. Pedersen. Biochemical and Biophysical Research Communications 324 (2004) 269–275

2. A Translational Study “Case Report” on the Small Molecule “Energy Blocker” 3-Bromopyruvate (3BP) as a Potent Anticancer Agent: From Bench Side to Bedside*. Ko, Y.H.1,2, Verhoeven, H.A.3, Lee, M.J.4, Corbin, D.J.5, Vogl,T.J.6, and Pedersen, P.L.1,7,8,

3. Kunjithapatham, R., Geschwind, JF., Rao, PP., Boronina, TN., Cole, RN and Ganapathy–Kanniappan, S. (2013). Systemic administration of 3–bromopyruvate reveals its interaction with serum proteins in a rat model. BMC Res Notes (in press)

4. Ota S, Geschwind JF, Buijs M, Wijlemans JW, Kwak BK, Ganapathy–Kanniappan S. Ultrasound–guided direct delivery of 3–bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer. Target Oncol. 2013 Mar 26. [Epub ahead of print] PubMed PMID: 23529644

5. Buijs M, Wijlemans JW, Kwak BK, Ota S, Geschwind JF. Antiglycolytic Therapy Combined with an Image–guided Minimally Invasive Delivery Strategy for the Treatment of Breast Cancer. J Vasc Interv Radiol. 2013 May;24(5):737–43. doi: 10.1016/j.jvir.2013.01.013. Epub 2013 Mar 13. PubMed PMID: 23489770

6. Ganapathy–Kanniappan S, Kunjithapatham R, Geschwind JF. Anticancer efficacy of the metabolic blocker 3–bromopyruvate: specific molecular targeting. Anticancer Res. 2013 Jan;33(1):13–20. PubMed PMID: 23267123

7. Ganapathy–Kanniappan S, Kunjithapatham R, Torbenson MS, Rao PP, Carson KA, Buijs M, Vali M, Geschwind JF. Human hepatocellular carcinoma in a mouse model:assessment of tumor response to percutaneous ablation by using glyceraldehyde–3–phosphate dehydrogenase antagonists. Radiology. 2012 Mar;262(3):834–45. doi: 10.1148/radiol.11111569. PubMed PMID: 22357885; PubMed Central PMCID: PMC3285229

8. Schaefer NG, Geschwind JF, Engles J, Buchanan JW, Wahl RL. Systemic administration of 3–bromopyruvate in treating disseminated aggressive lymphoma. Transl Res. 2012 Jan;159(1):51–7. doi: 10.1016/j.trsl.2011.08.008. Epub 2011 Sep 22. PubMed PMID: 22153810

9. Liapi E, Geschwind JF, Vali M, Khwaja AA, Prieto–Ventura V, Buijs M, Vossen JA, Ganapathy S, Wahl RL. Assessment of tumoricidal efficacy and response to treatment with 18F–FDG PET/CT after intraarterial infusion with the antiglycolytic agent 3–bromopyruvate in the VX2 model of liver tumor. J Nucl Med. 2011 Feb;52(2):225–30. doi: 10.2967/jnumed.110.083162. Epub 2011 Jan 13. Erratum in: J Nucl Med. 2011 Mar;52(3):495. PubMed PMID: 21233194

10. Ganapathy–Kanniappan S, Vali M, Kunjithapatham R, Buijs M, Syed LH, Rao PP, Ota S, Kwak BK, Loffroy R, Geschwind JF. 3–bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy. Curr Pharm Biotechnol. 2010 Aug;11(5):510–7. Review. PubMed PMID: 20420565

11. Ganapathy–Kanniappan S, Geschwind JF, Kunjithapatham R, Buijs M, Syed LH, Rao PP, Ota S, Kwak BK, Loffroy R, Vali M. 3–Bromopyruvate induces endoplasmic reticulum stress, overcomes autophagy and causes apoptosis in human HCC cell lines. Anticancer Res. 2010 Mar;30(3):923–35. PubMed PMID: 20393016

12. Ganapathy–Kanniappan S, Geschwind JF, Kunjithapatham R, Buijs M, Syed LH, Rao PP, Ota S, Vali M. The pyruvic acid analog 3–bromopyruvate interferes with the tetrazolium reagent MTS in the evaluation of cytotoxicity. Assay Drug Dev Technol. 2010 Apr;8(2):258–62. doi: 10.1089/adt.2009.0226. PubMed PMID: 20085459

13. Ganapathy–Kanniappan S, Geschwind JF, Kunjithapatham R, Buijs M, Vossen JA, Tchernyshyov I, Cole RN, Syed LH, Rao PP, Ota S, Vali M. Glyceraldehyde–3–phosphate dehydrogenase (GAPDH) is pyruvylated during 3–bromopyruvate mediated cancer cell death. Anticancer Res. 2009 Dec;29(12):4909–18. PubMed PMID: 20044597.

14. Liapi E, Geschwind JF. Interventional oncology: new options for interstitial treatments and intravascular approaches: targeting tumor metabolism via aloco–regional approach: a new therapy against liver cancer. J Hepatobiliary Pancreat Sci. 2010 Jul;17(4):405–6. doi: 10.1007/s00534–009–0236–x. Epub 2009 Nov Review. PubMed PMID: 19890602; PubMed Central PMCID: PMC3063000.

15. Vossen JA, Buijs M, Syed L, Kutiyanwala F, Kutiyanwala M, Geschwind JF, Vali M. Development of a new orthotopic animal model of metastatic liver cancer in the rabbit VX2 model: effect on metastases after partial hepatectomy, intra–arterial treatment with 3–bromopyruvate and chemoembolization. Clin Exp Metastasis.2008;25(7):811–7. doi: 10.1007/s10585–008–9195–x. Epub 2008 Jul 23. PubMed PMID: 18649116

16. Vali M, Vossen JA, Buijs M, Engles JM, Liapi E, Ventura VP, Khwaja A, Acha–Ngwodo O, Shanmugasundaram G, Syed L, Wahl RL, Geschwind JF. Targeting of VX2 rabbit liver tumor by selective delivery of 3–bromopyruvate: a biodistribution and survival study. J Pharmacol Exp Ther. 2008 Oct;327(1):32–7.doi: 10.1124/jpet.108.141093. Epub 2008 Jun 30. PubMed PMID: 18591216; PubMed Central PMCID: PMC2760588

17. Buijs M, Vossen JA, Geschwind JF, Ishimori T, Engles JM, Acha-Ngwodo O, Wahl RL, Vali M. Specificity of the anti–glycolytic activity of 3–bromopyruvate confirmed by FDG uptake in a rat model of breast cancer. Invest New Drugs. 2009Apr;27(2):120–3. doi: 10.1007/s10637–008–9145–0. Epub 2008 Jun 14. PubMed PMID:18553054

18. Vali M, Liapi E, Kowalski J, Hong K, Khwaja A, Torbenson MS, Georgiades C,Geschwind JF. Intraarterial therapy with a new potent inhibitor of tumor metabolism (3–bromopyruvate): identification of therapeutic dose and method of injection in an animal model of liver cancer. J Vasc Interv Radiol. 2007 Jan;18(1Pt 1):95–101. PubMed PMID: 17296709

19. Geschwind JF, Georgiades CS, Ko YH, Pedersen PL. Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev Anticancer Ther. 2004 Jun;4(3):449–57. Review. PubMed PMID:15161443

20. Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH. Mitochondrial bound type II hexokinase: key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta. 2002 Sep 10;1555(1–3):14–20. PubMed PMID: 12206885

21. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL. Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res. 2002 Jul 15;62(14):3909–13. PubMed PMID: 12124317

22. Ko YH, Pedersen PL, Geschwind JF. Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett.2001 Nov 8;173(1):83–91. PubMed PMID: 11578813.

In addition for the Warburg effect, glycolysis and Cancer:
1. http://sabatinilab.wi.mit.edu/Sabati...-Cell-2008.pdf
2. http://www.fundacion-barcelo.com.ar/...f%20cancer.pdf
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849637/
4. A figure showing where all things we know about Cancer meet: Regulation of cancer cell metabolism : Nature Reviews Cancer http://www.nature.com/nrc/journal/v1...rc2981_F2.html
5. From the Johns Hopkins: Understanding Cancer Energetics – 06/02/2011 http://www.hopkinsmedicine.org/news/...cer_energetics
6. Otto Warburg’s contributions to current concepts of cancer metabolism. Willem H. Koppenol, Patricia L. Bounds & Chi V. Dang. Nature Reviews Cancer 11, 325-337 (May 2011)
7. The Mitochondrial ATPase Inhibitory Factor 1 Triggers a ROS-Mediated Retrograde Prosurvival and Proliferative Response. Laura Formentini, Marıa Sanchez-Arago, Laura Sanchez-Cenizo, and Jose M. Cuezva. Molecular Cell 45, 731–742, March 30, 2012
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Old 25-06-2014, 09:56 AM   #619
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Why aren’t we focusing our efforts to find a Cure for Cancer

As a comment to the following story: http://www.cnn.com/2013/11/14/health...son/index.html

Greg wrote: Ever since seeing not only my mom die of cancer that had spread to every nook in her body, but also with my own battle with cancer, I have hoped that doctors could find a way to make sure they got every scrap of the tumor when it’s removed. My surgeons always warned me that while they may have removed the tumor, they can’t guarantee they removed the ENTIRE cancer; thus we have remission instead of cure. I hope Dr. Olson and his team win the Nobel Peace Prize for their amazing efforts. More so, as a cancer survivor I can’t begin to thank him enough for putting humanity first before profit. If the world stopped trying to pursue the man-made God called ‘Money’ for awhile and focused on working together, imagine the leaps and bounds that could be made in the world of medicine?

Dear Greg,

we have a Cure. It’s called 3-bromopyruvate, Glycobloc for short, and people are working on bringing it to the bedside. It’s a cheap drug and it obliterates tumors. There’s never been anything like it. It’s not a scum, a fad, something that may help, something that shows promise etc. It’s the real deal. Hundreds of scientists are working on it across the globe. Once the discovery has been made, everything else will follow, in fact progress is in the works and Glycobloc (3-bromopyruvate) is approved as an orphan drug for use in Clinical trials.

The question is how we as the public can speed up the process when thousands of lives are being lost every day. Pharmaceuticals and academic researchers make long-term (five to fifteen year) financial and career commitments on their area of study, on a therapy they believe in and they work based on fact and study as much as on intuition. They can’t just drop everything and go after one single thing. They have made a promise to study another thing and report their findings every year and they are accountable for working on something other than promised. If they don’t deliver on their grants the incremental progress that they have promised their peers they are in trouble and maybe out of a job, out in the streets etc. They’ve worked too hard and they are way too smart to deserve this.

Even if the single thing they could all work on is the true cure, researchers cannot all work on Glycobloc unless the funding agencies direct them to do so. Pharmaceuticals cannot work on Glycobloc because they are private companies and they need to make a profit and there is no profit on this, but they are working on analogs that may be profitable to them as well as beneficial to humanity. Doctors have a bit more leeway than basic researchers, little leeway into what they do outside established standard of care. If the public demands from their politicians and their government to speed up the process, the process will be sped up. If doctors are educated about this drug, they will increasingly be interested and involved.

The funding that pharmaceuticals cannot provide, philanthropists and funding agencies can. Why run for a cure, when the cure has been found unless the money is to go the Cure? Fund-raise but ask for the money to go where it will be most productive. If you know about Glycobloc, the agency you are fund-raising for will know about Glycobloc. Basic Science is great, of course, and all this incremental knowledge accumulated by all researchers does add up into a dividend for society and there is the story of Glycobloc itself to prove it. Glycobloc is the crowning jewel on 40 years of basic research by an old-time biochemist Dr Peter Pedersen and his post-doc Dr Kho. A team of Johns Hopkins interventional radiologists are going to implement its first Clinical trials.

The end of Cancer can be a grassroots movement, a crowd sourcing movement and angels will come. Yes, there are blocks to progress as this story of cancer cell paint proves but when something is really, really useful, in the end a break can be found. Cancer Research was championed by Mary Lasker, and in this story cancer cell paint was funded by a motivated mother. The possibilities today are brighter than ever before and as you say we should all work together to achieve the End with leaps and bounds now that it is possible.
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Old 25-06-2014, 10:06 AM   #620
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Glycobloc is the End to the War on Cancer

YOU end the War on Cancer

Lung Cancer is gone with aerosol treatment.
Breast Cancer is obliterated with drug injection.
Liver Cancer disappears with Intra-arterial administration.

It is not a dream. It is not Science Fiction. It is what 3-bromopyruvate, which we have termed Glycobloc, does in animal systems.

Shouldn’t Glycobloc be curing Cancer in humans? James Watson thinks so.

The same James Watson, who together with Francis Crick won the Nobel prize for deciphering the DNA structure writes in a recent article of Open Biology of the Royal Society Publishing : “….3-Bromopyruvate…has the capacity to truly cure….”. He also thinks: “….We must focus much, much more on the wide range of metabolic and oxidative vulnerabilities….of cancer cells….”.

So far, Glycobloc kills the wide range of human carcinoma cells tested.

In a recent humanitarian basis approved use of Glycobloc, a teenage patient in Germany received a single dose administration of Glycobloc while being in a state of coma, after having received all possible standard of care therapies. He came out of his coma and became a cancer-free Glycobloc advocate.

Glycobloc is a cheap drug with low toxicity, effective after a single dose. Glycobloc has the potential and the promise to become for Cancer what antibiotics became to tuberculosis. This Waterloo of Cancer was discovered by Johns Hopkins scientists and doctors.

If the Cancer can be seen on a PET-scan, it can be killed. 95% of all Cancers are detectable by PET scan, 95% of all Cancers can potentially be killed by Glycobloc.

To find out the scientific background about Glycobloc and see images of its miraculous actions on animal systems, you can view a talk at the NCI by one of Glycobloc’s discoverer’s Dr. Peter Pedersen at: http://videocast.nih.gov/summary.asp?Live=7542

Look for future postings on this blog that will also explain the Science behind this discovery. We will make clear how Glycobloc kills Cancer and why it is as effective a Cancer killing drug.

Championed by Pre-Science labs (http://presciencelabs.com/ as PSL-001) Glycobloc will soon enter Phase 1 Human Trials in liver cancer, fast-tracked by the FDA.

This is not enough. The public needs to be educated about the potential of this new therapy. Oncologists need to be educated about the potential of this agent. Public awareness must create demand for the application of this therapy to more organs. An explosion of clinical trials must be supported by angel and public funds.

The Emperor of all Maladies will kill 7,000,000 people worldwide this year, including 600,000 Americans. The fast-tracking of the drug comes ten years after its discovery. Sixty eight million people that could have potentially been cured by Glycobloc have died from Cancer in these ten years.

Even fast-tracking Clinical trials under the current guidelines is not enough. The young patient in Germany was cured of his cancer. He lived only another year. He died not from the Cancer but from the toxic molecules released by the cancer cells as they died. He died from a condition called Tumor Lysis Syndrome.

If the patients get treated after all else has failed, when the tumors are big enough to release massive amounts of toxic nitrogen and if the detoxifying function of the liver has been compromised, what use is it to cure the Cancer and lose the patient? Glycobloc must be used for early intervention, as soon as its efficacy in humans has been firmly demonstrated. This can only happen, if public awareness turns into public demand and educates policy.

I am an MIT trained Cancer Biologist and former Cancer Patient. If you have lost anyone to Cancer, if you have a loved one who is suffering from Cancer, just like me, you don’t want a single more life lost to this terrible disease.

This is why we need to support human clinical trials on Glycobloc.

The Cancer Cure LLC, is founded to educate the medical community, the general public and charitable private organizations as well as government funding agencies and policy makers about Glycobloc. We aim to precipitate the fast-track testing of Glycobloc on human cancers. Our official website and forum thetruecancercure.com will be launching in early 2014.

As a member of the general public….You can help us jumpstart this effort. You can help spread the word about The Cancer Cure. You can End the War on Cancer.

Every day that the Cure is delayed the death toll is rising. You can help save up to 1,643 lives per day in the US alone, and 19,100 lives per day worldwide. Help end the War on Cancer tomorrow, NOT in another ten or fifteen years.

In the era when Cancer is treated like an individual disease…or a hundred diseases…A single cure has become unthinkable and synonymous to quackery. Yet it is here and it is real.

The Cancer Cure is not quackery or hand-waving. The story of Glycobloc is a triumph of basic science, proving how the quest for scientific answers is the most productive route for society, just as Vannevar Bush believed.

The Cancer Cure, LLC will provide public education to educate the public, physicians and agencies for Glycobloc related Science and Glycobloc’s bench-side application. TheCancerCure LLC, will produce educational images and videos and carry out outreach efforts. The organization plans to fundraise for research and outreach. We are looking for institutional partners in our effort. If you are committed to ending the War on Cancer, supporting Glycobloc’s transition from bench to bed-side is the most productive thing you can do today.
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