Checkpoint Blockade with Neoantigen Cancer Vaccines for Personalized Immunotherapy

Methods for harnessing the exquisite specificity of the immune system to eliminate tumors have been under development since the start of the 20th century, with numerous studies in animal models and trials in humans. Despite accumulating evidence, there has been widespread skepticism in the cancer community about whether tumors could be controlled by spontaneous immunity, and whether effective immunotherapy would be feasible to develop. However, the field has now passed an inflection point as new results have quelled these doubts, including: (i) several large clinical studies that have identified infiltrating CD8+ T cells as one of the best predictors of overall survival in human cancers, with strong validation in a large study of colorectal cancers; (ii) adoptive T cell therapy that effectively eradicates some types of B cell leukemias and (iii) novel checkpoint blockade (CPB) therapies inducing unprecedented long-term cures for patients with solid tumors, and more recently with blood malignancies. With the availability of these novel immunologic agents, the priority has shifted to understanding the mechanisms of and predicting responses to each treatment. Fundamental to this endeavor is the understanding of the crosstalk between tumor cells and immune cell populations within the tumor microenvironment and the selective pressure they mutually exert on each other. At the heart of cancer and host immune cell coevolution is the tumor antigen and host antigen-specific T cell interaction. The cytotoxic T cell-cognate antigen interaction forms the mechanistic basis for immune-mediated recognition and the killing of malignant cells, and provides selective pressure on the cancer cell to evolve. While the search for immunogenic tumor antigens has been the subject of decades-long studies, multiple lines of evidence have convincingly demonstrated tumor neoantigens as an important class of immunogenic tumor antigens. Neoantigens arise from amino acid changes encoded by somatic mutations in the tumor cell and have the potential to bind to and be presented by personal HLA molecules. With the recent availability of next-generation sequencing, systematic approaches to identify mutations leading to amino acid changes have become feasible. This development, together with the improved sensitivity of well-validated neural network/machine learning-based algorithms that predict binding to class I MHC, has enabled the implementation of neoantigen discovery pipelines. Recent studies by us and others in humans and mice have leveraged these tools to demonstrate evidence of protective immunity when targeting tumor neoantigens. We have further incorporated this approach to discover antigen targets to generate a multi-epitope personalized therapeutic cancer vaccine, that we are now testing in phase I clinical trials. Altogether, effective targeting of tumor neoantigens occurs spontaneously and during CPB, and offers prospects of a powerful, new immunotherapy.