Teresa Ramirez-Montagut, M.D., Ph.D.
Cancer vaccines and cancer immunotherapy are a therapeutic possibility due to the recognition of tumor antigens by the host’s immune system. It has been demonstrated in pre-clinical and clinical studies that the immune system is able to recognize and mount antibody and T-cell responses against cancer, and in rare instances, even reject a tumor. The GNF’s Cancer Vaccine Initiative aims at understanding the biology of tumor rejection and identifying therapies to enhance anti-tumor immunity.
Cancer antigens are classified in four groups: unique antigens, cancer-testis antigens, differentiation antigens, and over-expressed antigens. Unique antigens are a series of neo-antigens that result from mutations that arise from the inherent genomic instability of tumors. Cancer-testis antigens are normally expressed in male germ cells and are silenced in healthy somatic cells, but are re-expressed in certain cancers. Differentiation antigens are present in both tumor cells and their normal cellular counterpart. Over-expressed antigens are present in healthy tissue, but are extensively represented in cancerous cells. Of these antigens, the most potent tumor-rejection antigens are unique antigens, but identification and creation of vaccines against unique antigens (excluding tumors caused by viruses) is hindered by the difficulty of developing individualized vaccines.
Overall, most cancer antigens are weak antigens since they are shared by tumors and normal tissues and are thus self-antigens. Although self-antigens should be invisible to the immune system, surprisingly, the large majority of tumor antigens characterized to date are unaltered-self antigens. Self-reactive T cells that escape thymic deletion become ignorant or anergic in the periphery when they encounter self-peptides in the absence of costimulation. However, a variety of strategies for cancer immunizations have been successful in breaking ignorance/tolerance to self and stimulate these low avidity T cells to reject tumors.
Vaccination strategies that successfully overcome tolerance do not guarantee that a tumor will be eradicated. A major hurdle for cancer immunotherapy resides in the tumor microenvironment that harbors suppressor regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and negative regulators of T-cell activation. In addition to these local factors that impair immune-meditated tumor killing, a second hurdle involves the actual tumor burden present in the host. Patients with a significant tumor mass undergo standard of care cytoreductive therapies that may hinder immune responses, however, recent studies have demonstrated that several chemotherapeutic agents may induce antigenic cell death and enhance immune recognition and eradication of tumors. Seminal to clinical incorporation of cancer immunotherapies alongside other oncological treatments is the demonstration that cancer vaccination is compatible and/or synergistic with chemotherapeutic agents.
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The Cancer Vaccine Initiative (CVI) takes advantage of a unique set of innovative technologies available within GNF and Novartis to target and enhance this naturally occurring, yet suboptimal, anti-tumor immunity. We are applying these technologies to:
- Cancer antigens: we are utilizing GNF’s innovative technologies to create modifications to tumor antigens that break self-tolerance and enhance anti-tumor responses.
- Adjuvant systems: we are applying Novartis Vaccine & Diagnostics unique adjuvant systems to cancer vaccination and we continue to develop immune potentiators that further enhance anti-tumor immune responses.
- Immunomodulators: we are developing high throughput screening coupled with small molecule and siRNA/cDNA library screens to identify druggable targets that are regulators of immune responses.
Novartis’s drug discovery efforts: we are testing in a highly optimized and systematic manner the compatibility of Novartis’s novel antineoplasic compounds with different cancer immunotherapies with the hope of identifying synergistic effects.