Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches

Abstract

In recent years, the use of immune checkpoint inhibitors (ICIs) in combination with approved or experimental vaccines has proven to be a promising approach to improve vaccine immunogenicity and efficacy. This strategy seeks to overcome the immunosuppressive mechanisms associated with the vaccine response, thereby achieving increased immunogenicity and efficacy. Most of the information on the use of ICIs combined with vaccines derives from studies on certain anti-tumor vaccines combined with monoclonal antibodies (mAbs) against either cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1). However, over the past few years, emerging strategies to use new-generation ICIs as molecular adjuvants are paving the way for future advances in vaccine research. Here, we review the current state and future directions of the use of ICIs in experimental and clinical settings, including mAbs and alternative new approaches using antisense oligonucleotides (ASOs), small non-coding RNAs, aptamers, peptides, and other small molecules for improving vaccine efficacy. The scope of this review mainly includes the use of ICIs in therapeutic antitumor vaccines, although recent research on anti-infective vaccines will also be addressed.

Keywords: CTLA-4; PD-1; PD-L1; antisense oligonucleotides; aptamers; immune checkpoint inhibitors; molecular adjuvants; monoclonal antibodies; peptides; vaccines.

Figure 1

The Cancer-Immunity cycle is a process summarized in seven steps, which is initiated by the release of antigens from cancer cells and the activation of various immune mechanisms that ends with the elimination of cancer cells. The existence of negative feedback mechanisms developed both during the regulatory phase of the immune response (A), and by tumors to escape from the immune control (B), hinders this cycle and can be a hurdle to the development of effective immunotherapies. The goal of ICIs is to block critical immunosuppressive regulatory mechanisms and enhance effector T cells for the maintenance of the cycle of immunity against cancer. CTLs: Cytotoxic T lymphocytes; DC: Dendritic cell; MHC-I/MHC-II: Major Histocompatibility Complex Class I or II; PD-1: Programmed Death 1; PD-L1/2: Programmed Death-ligand either 1 or 2; Th: Helper T Cells; Treg: Regulatory T cell.