A novel cellular immunotherapy using vaccine generated neoantigen-specific effector T cells.

Abstract

2537 Background: Cellular immunotherapy languished in obscurity until genetically engineered chimeric antigen receptor T cells were shown to effectively treat B lymphocyte cancers. Genetic studies also revealed that some cancer cell mutations produce neoantigens, which are consistent with historical studies demonstrating that cancer cell vaccination generates neoantigen specific immune responses in rodents and humans. Vaccination leads to an increase in neoantigen-specific T cells in lymphoid tissue that are released into the blood, which carries them to sites of disease activity, e.g., cancer tissue. TVAX Biomedical hypothesized that the natural power of the patient’s immune system could be exploited using a novel neoantigen-specific cellular immunotherapy. Methods: Patients are vaccinated with their own attenuated cancer cells plus an immunologic adjuvant, e.g. GM-CSF, to increase the number of circulating neoantigen primed T cells. Patients are leukapheresed to collect the T cells. The collected T cells are exposed to activation and proliferation stimulating agents to generate the neoantigen-specific effector T cells that are used for treatment. TVAX is currently testing this treatment paradigm for efficacy and safety in newly diagnosed (MGMT-negative) glioblastoma patients when they have minimized immunosuppression and minimal residual disease, TVI-AST-008. Results: For this novel cellular immunotherapy to be effective, T cell mediated immune responses must be generated in vaccinated patients. Delayed type hypersensitivity skin testing, a method for detecting T cell mediated immunity in humans, showed reactions in patients with leukemia, brain, breast, colon, lung, kidney, melanoma, ovarian, prostate and sarcoma (data to be presented). Multiple autologous vaccinations led to detectable responses in all patients. The combination of cancer cell/immunologic adjuvant vaccination plus neoantigen-specific T cellular immunotherapy has been shown to be highly effective against a wide range of cancer types in preclinical studies and to be effective against the least immunogenic cancers. Conclusions: The possibility that neoantigen-specific T cells could effectively treat some human cancers has been documented through studies with tumor infiltrating lymphocytes (TILs). However, TIL efficacy is limited to a small number of (hot) cancers. Preclinical model studies demonstrated that neoantigen-specific effector T cells enter cancer tissue, initiating a cascade of T cell mediated immunologic events that ultimately leads to killing of cancer cells by cytotoxic T cells and cytokine activated accessory cells. The benefit of the vaccine enhanced neoantigen-specific effector T cell therapy (TVAX Immunotherapy) is that it expands the range of human cancers that could be safely and effectively treated. Clinical trial information: 05685004.