In a study reported in Nature, Gubin and colleagues showed that the effects of CTLA-4 (cytotoxic T-lymphocyte–associated protein-4) and PD-1 PD-1 (programmed cell death protein-1) inhibitors (checkpoint blockade) are achieved through targeting of tumor-specific mutant antigens. In the study, genomic and bioinformatic approaches identified tumor-specific mutant proteins as a major class of T-cell rejection antigens following anti–PD-1 or anti–CTLA-4 treatment of mice with progressively growing sarcomas. Synthetic therapeutic long-peptide vaccines incorporating the mutant epitopes resulted in tumor rejection comparable to that observed with checkpoint blockade immunotherapy. It was observed that although mutant tumor antigen-specific T cells were present in progressively growing tumors, they were reactivated with anti–PD-1 or anti–CTLA-4 antibody treatment; the T cells displayed some overlapping transcriptional profiles but primarily expressed treatment-specific profiles that were associated with tumor rejection.
The investigators concluded: “These results reveal that tumor-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.” ■
Gubin MM, et al: Nature 515:577-581, 2014.