Development, Validation and Optimization of Combinatorial Cancer Immunotherapy Using Personalized Neoantigen Vaccines Together with Monoclonal Antibodies Targeting Immune Checkpoints

Abstract

Among the current strategies to use the immune system to treat cancer patients, the blockade of immune checkpoints has yielded highly encouraging results in several clinical trials. Recent work in Dr. Schreiber`s laboratory has used a combination of next generations sequencing, bioinformatics and state-of-the-art immunology techniques to shown that tumor specific T cells reactivated upon checkpoint blockade preferentially react with epitopes of mutant tumor antigens. The work in the Schreiber lab has also led to the development of distinct families of carcinogen induced mouse sarcomas that (a) are rejected spontaneously when injected into naïve syngeneic wild type mice; (b) grow progressively in wild type mice but are rejected when tumor-bearing mice are treated with either anti-CDTLA-4, anti-PD-1, or a vaccine consisting of synthetic long tumor-specific mutant neoepitope administered as mono- or combination-therapies; or (c) are not rejected when tumor bearing mice are treated with checkpoint blockade or tumor specific vaccines but whose growth can be controlled partially when mice are treated combinations of anti-CTLA-4, anti-PD-1 and/or synthetic long neoepitope vaccines. Preliminary data suggest that therapeutic control of this third group can be improved if we can improve the efficacy of our vaccination protocols. Thus in this project, we wish to formally test the hypothesis that more efficient vaccination methods would improve the therapeutic outcome of checkpoint blockade immunotherapy. For this purpose, we aim to explore the following types of tumor-specific antigen vaccines: synthetic long peptides containing additional predicted neoantigens from the tumors, double attenuated Listeria vaccines, DNA vaccine and dendritic cells fed with neoepitopes peptides.