Novel Combination Strategies to Enhance Immune Checkpoint Inhibition in Cancer Immunotherapy: A Narrative Review

Abstract

Programmed cell death protein-1 (PD-1) is an immune checkpoint receptor that induces and maintains tolerance of T cells, invariant natural killer T (iNKT) cells, and natural killer (NK) cells, among other lymphocytes. Immune checkpoint inhibition by PD-1 blockade restores the lymphocytic immunostimulatory phenotype and has been successful in the treatment of various malignancies. However, while immune checkpoint blockade has been shown to provide robust antitumor treatment outcomes, its overall response rate remains low in a significant portion of cancer patients. An essential unmet need in cancer therapy is the development of novel pharmacologic strategies designed to lower rates of resistance associated with immune checkpoint blockade. Therefore, efforts that seek to enhance the efficacy of PD-1 inhibition possess profound immunotherapeutic potential. Here, three promising combination strategies that harness the antitumor effects of immune checkpoint inhibitors (ICIs) together with non-ICI antitumor therapeutic agents are reviewed. These agents include (1) ABX196, a potent inducer of iNKT cells, (2) chimeric antigen receptor (CAR)-T cell therapy, and (3) NK cell therapy. A comprehensive literature search was conducted using the PubMed and ClinicalTrials.gov databases for scientific articles and active trials, respectively, pertaining to immune checkpoint inhibition, iNKT cells, CAR-T cells, and NK cell immunotherapy. Preliminary clinical and preclinical data suggest that these combination treatment regimens greatly suppress tumor growth and may serve as innovative methods to enhance and optimize anticancer immunotherapy.