Cancer immunotherapy: moving forward with peptide T cell vaccines

Abstract

Recent advances in cancer immunology, such as the discovery of immune checkpoint inhibitors, have validated immune cells as potential key players for effective cancer treatment. The efficacy of these therapies seems to be codependent on a tumor-reactive T lymphocyte response. For many years, numerous attempts and strategies in developing vaccines to generate tumor-reactive T cells have yielded poor results in the clinic due to suboptimal immunogenicity and the inability to overcome an immunosuppressive tumor microenvironment. In this review, we summarize past and current advances in T cell vaccines and describe our experience in developing optimized methods for antigen/adjuvant selection and vaccine administration in order to induce powerful anti-tumor responses.

Figure 1. Rational path to designing and testing effective T cell epitope-based vaccines for cancer

The goals of tumor vaccines are to induce strong and lasting antitumor T cells that can recognize and kill tumor cells (A), and overcome immunosuppression in the tumor microenvironment (B). The 4 steps to develop the vaccines: 1) Epitope selection is critical to develop effective T cell epitope-based vaccines. TAg potential epitopes that bind to an MHC molecule are predicted using computer-based algorithms and can be validated with binding assays. The presence of the peptide epitope on tumor cells can be assessed with mass spec sequencing of MHC eluted peptides. Epitope immunogenicity is established by in vitro T cell stimulation assays or in vivo by vaccinating HLA transgenic mice. 2) To enhance immunogenicity the amino acid sequence of epitope can be modified to increase MHC binding or enhance amphiphilicity. 3) The selection of appropriate adjuvants, costimulatory agonists and cytokines will determine the magnitude and duration of the T cell responses. 4) The mode of vaccine administration (injection route, boosters) and the possibility combining the vaccine with adjunct treatments are factors to consider for achieving effective antitumor responses. The immunogenicity and effectiveness of vaccines should be monitored by measuring realistic antitumor effects in vivo (a), changes in TAg-specific T cells pre- and post-vaccination (b), assessing T cell reactivity to tumor cells (c), infiltration of T cells in tumors (d), and evaluating skin delayed type hypersensitivity (DTH) responses in the vaccinees.