Diverse Neoantigens and the Development of Cancer Therapies

Abstract

Cancer is the manifestation of uncontrolled cellular growth and immune escape mechanisms. Unrestrained tumor growth can be associated with incidental errors in the genome during replication and genotoxic agents can alter the structure and sequence of our DNA. Among all genetic aberrations in cancer, only limited number of mutations can produce immunogenic antigens which have the potential to bind human leukocyte antigen class I or human leukocyte antigen class II, and help activate the adaptive immune system. These neoantigens can be recognized by CD8⁺ and CD4⁺ neoantigen-specific T lymphocytes. Recently, several immune checkpoint targeting drugs have been approved for clinical use. Primarily, these drugs expand and facilitate the cytotoxic activity of neoantigen-specific T cells to eradicate tumors. Differential drug response across cancers could be attributed, at least in part, to differences in the 'tumor antigen landscape' and 'antigen presentation pathway' in patients. Although tumor mutational burden correlates with response to immune checkpoint inhibitors in many cancer types and has evolved as a broad biomarker, a comprehensive understanding of the neoantigen landscape and the function of cognate T cell responses is lacking and is needed for improved patient selection criteria and neoantigen vaccine design. Here, we review cancer neoantigens, their implications for antitumor responses, the dynamics of neoantigen-specific T cells, and the advancement of neoantigen-based therapy in proposed clinical trials.