Enhancing Cancer Immunotherapy by Intracellular Delivery of Cell-Penetrating Peptides and Stimulation of Pattern-Recognition Receptor Signaling

The importance of T-cell-mediated antitumor immunity has been demonstrated in both animal models and human cancer immunotherapy. In the past 30 years, T-cell-based immunotherapy has been improved with an objective clinical response rate of up to 72%. Identification of MHC class I- and II-restricted tumor antigens recognized by tumor-reactive T cells has generated a resurgence of interest in cancer vaccines. Although clinical trials with cancer peptide/protein vaccines have only met a limited success, several phase II/III clinical trials are either completed or ongoing with encouraging results. Recent advances in immunotherapy have led to the approval of two anticancer drugs (sipuleucel-T vaccine and anti-CTLA-4 antibody) by the US FDA for the treatment of metastatic castration-resistant prostate cancer and melanoma, respectively. Intracellular delivery of antigenic peptides into dendritic cells (DCs) prolongs antigen presentation of antigen-presenting cells to T cells, thus further improving clinical efficacy of peptide/protein cancer vaccines. Because innate immune responses are critically important to provide sensing and initiating of adaptive immunity, combined use of cell-penetrating peptide vaccines with stimulation of innate immune signaling may produce potent antitumor immune responses. We will discuss the recent progress and novel strategies in cancer immunotherapy.