Cancer Vaccine Approaches: A Race For Dominance In The Field

by: Andrew J. Norris

Cancer vaccines are medicines that stimulate or restore the immune system's ability to fight an existing cancer by strengthening the body's natural defenses against the cancer cells. Cancer vaccines are similar to traditional vaccines, which help prevent infectious diseases, such as polio or measles, which protect the body against infection. Developing effective cancer treatment vaccines requires a detailed understanding of how immune system cells and cancer cells interact. The immune system often does not "see" cancer cells as dangerous or foreign, as it generally does with microbes. Therefore, the immune system does not mount a strong attack against the cancer cells not to mention cancer stem cells.

Both cancer vaccines and traditional vaccines are based on antigens that are carried by foreign agents and that are relatively easy for the immune system to recognize as an "outsider." Several factors may make it difficult for the immune system to target growing cancers for destruction. Most important, cancer cells carry normal self-antigens (self-markers) in addition to specific cancer-associated antigens. Furthermore, cancer cells sometimes undergo genetic changes that may lead to the loss of cancer-associated antigens. Finally, cancer cells can produce chemical messages that suppress anticancer immune responses by cells known as killer T cells which play a central role in cell-mediated immunity. As a result, even when the immune system recognizes a growing cancer as a threat, the cancer may still escape a strong attack by the immune system.

Producing effective treatment vaccines has proven quite challenging and to be effective, they must achieve two goals. First, like traditional vaccines, cancer vaccines must stimulate specific immune responses against the correct target. Second, the immune responses must be powerful enough to overcome the barriers that cancer cells use to protect themselves from attack by B cells and killer T cells. Recent advances in understanding how cancer cells escape recognition and attack by the immune system are now giving developers the knowledge required to design cancer treatment vaccines that can accomplish both goals.

The rational approach to cancer vaccine design has primarily taken three different approaches to targeting cancer cells via (A) single antigens (B) tumor lysate vaccines that take entire proteins from tumor and create a very broad response, and (C) multiple antigens, targeting dominant antigens present on tumors.

Vaccines based upon single antigens: This technology is represented by products such as Stimuvax® by Oncothyreon Inc. (ONTY) ‎ and Rindopepimut® (CDX-110) by Celldex Therapeutics, Inc. (CLDX) which each target a specific antigen on tumor cells. Stimuvax® is a next generation therapeutic vaccine designed to stimulate an individual's immune system to recognize cancer cells and control the growth and spread of cancers in order to increase the survival of cancer patients. Stimuvax® incorporates a small portion of the cancer-associated marker MUC-1 in a liposomal formulation, thus it is proposed to stimulate a T-cell mediated immune response to cancer cells expressing this antigen. The recent phase II study for Patients with Non-Small Cell Lung Cancer resulted in approximately twice as many patients still alive at three years in the Stimuvax® arm compared with the standard of care alone, representing a 45% reduction in mortality. The Phase III trial involving 1,514 patients is designed to show that Stimuvax® improves survival by at least 6 months in newly-diagnosed lung cancer patients who have tumors confined to the chest cavity, but are not eligible for surgery. Results are due in the second half of 2012. Oncothyreon has licensed the vaccine, Stimuvax®, to Germany's Merck KGaA (OTCPK:MKGAF), which is conducting the Phase III trial. Rindopepimut® (CDX-110) is an immunotherapy that designed to activate the patient's own immune system against tumor cells expressing EGFRvIII, an activated mutation of the epidermal growth factor receptor (EGFR) which is a protein that has been well validated as a target for cancer therapy. While many different tumors express this antigen, Glioblastoma multiforme (GBM), the most common and most aggressive malignant primary brain tumor in humans, is the first indication sought for approval. CDX-110 has just received fast track status and is currently in Phase III clinical trials. The Phase IIa study in GBM patients showed a median survival time of 30 months which is greater than a 100 percent increase in survival, versus the historical control's median of 14.5 months, an impressive result. In September 2011, Celldex Therapeutics enrolled its first patient into a Phase II/III randomized study of CDX-110 with radiation and temozolomide in patients with newly-diagnosed GBM. The clinical trial is investigating the anticancer activity, impact on survival, and safety of the addition of CDX-110 vaccine to standard of care, versus standard of care alone. Celldex Therapeutics recently announced that CDX-110 has also been granted Orphan Drug Status by the FDA which will give it a 7-year marketing exclusivity to recoup its costs among other benefits. In addition to these, the first cancer vaccine approved in 2010, sipuleucel-T [Provenge®], developed by Dendreon Corporation (DNDN) and GlaxoSmithKline (GSK) is also represented in this category as an vaccine for androgen independent prostate cancer.

Tumor lysate vaccines: This technology involves taking entire proteins from tumor for the purposes of creating a very broad immune response. DCVax®-L by Northwest Biotherapeutics (OTC:NWBO) is a dendritic cell immunotherapy product currently in Phase II studies also targeting the most lethal form of brain cancer, GBM, where the vaccine has doubled the median survival time. The Phase I data, based on work done here at UCLA, has shown significant improvement in patient survival. If the Phase II results are as significant as in the early stage trials, the company anticipates petitioning the FDA for an early approval of DCVax-L. This technology is based upon the use of dendritic cells (DCS), which are the most powerful immunostimulatory cells specialized in the induction and regulation of immune responses. DCVax®-L vaccine is manufactured from a patient's own white blood cells, which are exposed to cells from the patient's tumor so they "learn" to recognize brain cancer cells. When re-injected into the patient, the vaccine's white blood cells direct the immune system to recognize antigens associated with GBM. A second product, DCVax®- Prostate, which targets hormone independent prostate cancer, has also been cleared by the FDA to commence a Phase III clinical trial, which is also designed and powered as a pivotal trial for the drug. DCVax®-Prostate vaccine was recently cleared by the FDA for a 612-patients Phase III trial for non- metastatic hormone independent prostate cancer patients and the Company is looking for a partner to initiate the Phase III trial due to the scale of resources required for such a large trial. Manufacture of a DCVax product takes approximately 30 days to complete for DCVax®-Prostate and approximately 8- 10 days for DCVax®-L. OncoVEXGM-CSF, by BioVex Inc, now owned by Amgen (AMGN), (GNCSF (adjuvant) + virus vector into the tumor itself) is a 2nd generation oncolytic herpes simplex type 1 virus, encoding human GM-CSF. OncoVEXGM-CSF touts improvement over previous vaccine and virus-based approaches for the treatment of cancer. This is because the virus vector used has been genetically reprogrammed to attack cancerous cells, while healthy cells remain undamaged. While OncoVEXGM-CSF is administered locally by intra-tumoral injection, it is believed to provide a systemic benefit by the induction of a potent anti-tumor immune response assisting in the eradication or prevention of new lesions elsewhere in the body. The use of GM-CSF in this drug is seminal to its mediation of dendritic cell function towards anticancer activity. GM-CSF is the principal mediator of proliferation, maturation, and migration of these DCs. As mentioned, DCs are the most potent antigen presenting cells of the immune system and by augmenting antigen presentation to lymphocytes by DCs, GM-CSF stimulates T-cell mediated immune responses, providing the basis for its potential as a systemic (throughout the body) anticancer therapy.

Multiple antigen targeting: Here well-established dominant antigens present on tumors are targeted via eliciting a specific T cell response against all those antigens. Products like this are represented by ICT-107 developed by Immunocellular Therapeutics Ltd. (IMUC) which targets not one, but multiple antigens (gp100, MAGE‐1, IL‐13Rα2, Her‐2/neu, AIM‐2 and Trp‐2) that are significantly over‐expressed in GBM, as well as other cancers such as breast, colon, ovarian, skin (melanoma). What makes this approach unique and probably one of the more novel sides to its application is the targeting of cancer stem cells via those antigen choices. Cancer stem cells are rapidly being recognized as responsible for recurrence of tumors after primary treatment. This fact may possibly be reflected in the survival numbers which differ highly from any existing treatment for GBM. For phase I, 40% of treated patients are still free of disease over 3-4 years to date, which GBM experts agree is unusual. For ICT-107 design, the antigens targeted (IL‐13Rα2, Her‐2/neu, AIM‐2 and Trp‐2) are highly expressed on cancer stem cells preferentially over cancer daughter cells. This drug is currently completing Phase II studies for the primary indication of GBM. IMA901 by Immatics Biotechnologies GmbH, a private biopharmaceutical company based in Tuebingen, Germany, is also represented in this category as a combination of multiple tumor-associated peptides (TUMAPs) for the treatment of renal cell carcinoma. The recent Phase II study for advanced/metastatic renal cell carcinoma on patients who had failed previous first line therapy showed strong results in overall survival (OS) versus patients who did not receive the drug with the data being comparable to previous studies of the highly effective tyrosine kinase inhibitors sunitinib (Sutent®) Pfizer, Inc. (PFE) and sorafenib (Nexavar®) (co-developed and co-marketed by Bayer (OTN: BAYRY) and Onyx Pharmaceuticals (ONXX) as Nexavar®). IMA901 is currently in Phase III clinical trials.

Out of the approaches mentioned, each of these drugs is in differing phases of clinical development and it is not clear which approach is the best. As previously stated cancer cells sometimes undergo genetic changes that may lead to the loss of cancer-associated antigens and with focusing on a single target, there is this possibility (for example, the loss of tumor antigens EGFRVIII has been demonstrated in a GBM trial at Duke University). As the development of single antigen technology further progresses, this will become clear.

Although tumor lysate technology seeks to address this concern, it also can suffer from lack of specificity. Considering that antigens on the tumor itself are used to generate the response, not all the antigens are necessarily optimal or cancer related. The issues to face are a lack of specificity in terms of tumor antigens vs. normal antigens. Currently there is a lack of comparative data in a controlled setting comparing tumor lysate vs. single antigens but as the clinical data progresses, this will also become more clear. Immunocellular Therapeutics did appear to have this inquiry early on in its clinical development direction and as such, a comparative study at Cedars Sinai Hospital (Los Angeles, California) with an analogous tumor lysate vaccine against ICT-107 was conducted in Glioblastoma patients with similar levels of tumor resection. The comparison was conducted looking at both progression free survival (NYSE:PFS) as well as overall survival (OS) for ICT-107 vs. a tumor lysate approach. Significant increase in median PFS = 16.9 months for ICT‐107 were detected vs. 9.3 months for tumor lysate vaccine. Also, significant increase in median OS: 38.4 months for ICT‐107 vs, 20.2 months for tumor lysate vaccine were also observed. The results indicated an 18 month survival benefit of ICT-107 over its comparable tumor lysate vaccine in this controlled study. This data seems to indicate that targeting multiple well understood antigens relating to a particular cancer will maximize the responsiveness to the therapeutic while minimizing the possibility of CSC's doing what they do best, evasion. Lastly, the benefit of targeting several dominant antigens such as ICT-107 and IMA901 also waits to be seen if this is an advantage over other technologies. How this approach may develop in the future is open to speculation but one could consider therapeutics strategies targeting 4-5 dominant antigens for a particular cancer creating a laser like response in combination with conventional therapies. The big advantage of this strategy is to maximize immune response to dominant antigens and to minimize the possibility that all these antigens will be able to mutate and evade an immune response.

Disclosure: I am long IMUC.