Getting personal with neoantigen-based therapeutic cancer vaccines

Abstract

Despite years of preclinical efforts and hundreds of clinical studies, therapeutic cancer vaccines with the routine ability to limit or eliminate tumor growth in humans have been elusive. With advances in genome sequencing, it is now possible to identify a new class of tumor-specific antigens derived from mutated proteins that are present only in the tumor. These "neoantigens" should provide highly specific targets for antitumor immunity. Although many challenges remain in producing and testing neoantigen-based vaccines customized for each patient, a neoantigen vaccine offers a promising new approach to induce highly focused antitumor T cells aimed at eradicating cancer cells.

Figure 1

A, tumor neoantigens may be ideal targets for a therapeutic vaccine. Tumor neoantigens (top right) are present in tumor cells but not normal cells and do not induce deletion of their cognate antigen-specific T cells in the thymus (i.e., central tolerance). In these 2 dimensions, they appear more comparable with pathogen-derived antigens (top left) than to self-antigens (bottom left). In contrast, the most commonly identified and used tumor antigens (bottom middle) are selectively overexpressed in the tumor but can have residual expression in nontumor cells and induce central tolerance in the thymus. B, a therapeutic vaccine strategy based on tumor neoantigens. First, tumor mutations are discovered rapidly through DNA and RNA sequencing of tumor and normal tissue. Second, personalized tumor-specific mutated peptides are identified on the basis of predictive HLA-binding algorithms. Third, peptides based on neoORFs and missense neoantigens are synthesized. Finally, the peptides are delivered to patients with a powerful immune adjuvant and coupled with complementary immunotherapeutics, such as checkpoint-blockade inhibitors.