Therapeutic cancer vaccines: Where are we now?

An effective antitumor immune response is often associated with the presence of T cells directed toward cancer neoepitopes, a class of major histocompatibility complex (MHC)-bound peptides that arise from tumor-specific mutations. However, tumors frequently use multiple mechanisms to evade cytotoxic T lymphocyte (CTL) recognition and destruction. Among these mechanisms, defects in genes relevant for antigen presentation by MHC class I molecules to CD8+ T lymphocytes, such as loss of β2m and alterations in transporter associated with antigen processing (TAP), play a major role by inducing a sharp decrease in surface expression of MHC-class I/β2m-peptide complexes. Therefore, developing therapeutic cancer vaccines based on tumor neoantigens that are selectively presented by cancer cells carrying defects in antigen processing and presentation was a major challenge over the last two decades. In this regard, we have previously identified a non-mutant tumor neoepitope, ppCT16-25, derived from preprocalcitonin (ppCT) leader sequence and processed independently of proteasomes/TAP by a novel mechanism involving signal peptidase (SP) and signal peptide peptidase (SPP). We have recently shown that most human lung tumors display altered expression of TAP and frequently express ppCT self-antigen. ppCT includes several HLA-A2-restricted T-cell epitopes that are processed by proteasome/TAP-independent and -dependent pathways. We have also provided in vitro and in vivo proof of concept of an active immunotherapy based on ppCT-derived peptides capable of controlling growth of immune-escaped tumors expressing low levels of MHC-class I molecules. Non-mutant and mutant neoepitopes are promising targets for therapeutic cancer vaccines in combination with immune checkpoint inhibitors, such as anti-PD-1.