Sep 12, 2011
By Jedd D. Wolchok, MD, PhD
Memorial Sloan-Kettering Cancer Center
The notion of a vaccine to prevent or control solid tumors is inherently attractive based on the success of prophylactic immunization against a wide variety of infectious pathogens and the perceived specificity and low toxicity of vaccine monotherapy.
To get the “low-hanging fruit” out of the way immediately, let’s deal with malignancies caused by viral infections, which have effective and approved vaccines available (human papillomavirus [HPV] and hepatitis B virus [HBV]). These represent evidence that “yes, we can do it” as prophylactic immunization against oncogenic HPV and HBV will certainly decrease the incidence of these malignancies.
However, these represent relatively easy targets for the immune system as the antigens are inherently foreign and therefore highly immunogenic. For the average solid tumor, most of what the immune system “sees” is a spectrum of self antigens, which are shared with the normal tissue counterpart and subject to immunologic ignorance and tolerance. The challenges to cancer immunologists are to: 1) devise strategies to overcome ignorance and tolerance and/or 2) identify antigenic targets that are not routinely expressed on normal tissues (cancer testis antigens, neo-antigens from fusion proteins [BCR-ABL], mutational antigens).
Enhancing the immunogenicity of self antigens
Enhancing the immunogenicity of self antigens can be envisioned to occur through a variety of mechanisms. One is to use an altered form of the antigen. My research team and others have explored this strategy using xenogeneic or cross-species immunization, in which an orthologue from another species is used for vaccination.1 An example is the use of human tyrosinase DNA in dogs with metastatic melanoma. Dog tyrosinase is 90% identical to human, yet the 10% difference appears to be sufficient to suggest to the dog’s immune system that this is non-self. This strategy has led to the licensure of the tyrosinase DNA vaccine by the U.S. Department of Agriculture as the first therapeutic cancer vaccine in the United States.2,3 Studies using mouse antigen–based vaccines are currently being conducted to establish if a similar strategy is useful in humans.
Another strategy to enhance immunogenicity against self antigens on cancer is to express the antigen in a viral vector, such as a poxvirus, adenovirus, or alphavirus backbone.4,5 The viral proteins in the vector may provide immunologic “help” due to their inherent immunogenicity, and the viral polymerases may have imperfect fidelity, leading to the production of altered antigens with improved immune responses resulting from the creation of improved epitopes. Currently, apoxvirus-based prostate cancer vaccine is being investigated in late-stage clinical trials after initial studies suggested that overall survival is improved with the use of such a vaccine.6
Vaccines also may be combined with other immune modulators to enhance potency. The success of sipuleucel-T for prostate cancer attests to the utility of a cell-based product to improve immunity to prostatic acid phosphatase (PAP), a self antigen. This product, recently licensed by the FDA, is based on expression of PAP fused to granulocyte-macrophage colony-stimulating factor (GM-CSF).7 The fusion protein is incubated with autologous peripheral blood mononuclear cells as a source of antigen-presenting cells. A variety of other strategies, including the use of cytokines, double-stranded RNA, and pathogen-derived materials, are currently undergoing investigation for their ability to act as immunologic adjuvants for cancer vaccines.
“Holy grail” of cancer antigen identification
The “holy grail” of cancer antigen identification is the use of a target derived from an oncoprotein. This would be a way of directly addressing cells thatspecifically harbor a mutated oncogene. If a specific mutation responsible for contributing to malignant transformation was identified, it clearly would be an excellent choice as a potential target for a cancer vaccine. For example, attention has been paid to the V600E mutation in BRAF given its strong association with cutaneous melanoma. Investigators are exploring the sequence to see if the specific mutation allows for enhanced binding to major histocompatibility complex (MHC) molecules compared with the wild-type BRAF protein. Vaccines targeting HER2/neu are based on such a principle if alterations of HER2 could induce immunity to this functionally important, over-expressed self antigen. Oncogenic fusions such asBCR/ABL also are attractive vaccinetargets since the precise area ofthe fusion represents a non-selfneo-antigen not expressed by thenormal cell counterpart.8
There is also a class of proteins known as cancer/testis (C/T) antigens which, as the name implies, are only expressed on normal spermatozoa and a variety of malignancies. Transcription silencing occurs in other adult normal tissues; they are not subject to peripheral tolerance given the immunologically privileged nature of the testis. Two of these C/T antigens are MAGE-A3 and NY-ESO-1, which are both being studied in clinical trials for a variety of malignancies.9
The development of a successful preventive or therapeutic cancer vaccine for solid tumors clearly is an important goal. We have learned much about what prevents immunity to antigens on cancer and some novel strategies have emerged to address them. We can envision therapeutic vaccines as part of a more complex therapeutic program, including the use of more global immune modulators, such as CTLA-4 blocking antibodies.10 Routine use of combination approaches, which introduce additional possibilities for toxicity, likely will be problematic in the preventive setting where healthy but at-risk patients will be the population. In this setting, the urgency is to identify more immunogenic antigens specifically related to the malignant phenotype.
Dr. Wolchok is a medical oncologist and melanoma specialist at Memorial Sloan- Kettering Cancer Center. He is a member of the Journal of Clinical Oncology Editorial Board and serves on the Grants Selection Committee for the Conquer Cancer Foundation of ASCO. Dr. Wolchok was the lead author on an abstract selected for the 2011 ASCO Annual Meeting Plenary Session—Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma (Abstract LBA5).
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- Bergman PJ, Camps-Palau MA, McKnight JA, et al. Vaccine. 2006;24:4582-5. Epub 2005 Aug 24.
- Bergman PJ, McKnight J, Novosad A, et al. Clin Cancer Res. 2003;9:1284-90.
- Kim CJ, Prevette T, Cormier J, et al. J Immunother. 1997;20:276-86.
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- Kantoff PW, Schuetz TJ, Blumenstein BA, et al. J Clin Oncol. 2010;28:1099-105.
- Kantoff PW, Higano CS, Shore ND, et al. N Engl J Med. 2010;363:411-22.
- Jain N, Reuben JM, Kantarjian H, et al. Cancer. 2009;115:3924-34.
- Gnjatic S, Nishikawa H, Jungbluth AA, et al. Adv Cancer Res. 2006;95:1-30.
- Hodi FS, O’Day SJ, McDermott DF, et al. N Engl J Med. 2010;363:711-23.
Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology.