New Clinical Approaches and Emerging Evidence on Immune-Checkpoint Inhibitors as Anti-Cancer Therapeutics: CTLA-4 and PD-1 Pathways and Beyond.

Abstract

Background-The development of immune checkpoint blockers, primarily comprising the anti-PD-1/an-ti-PD-L1 and anti-CTLA-4 monoclonal antibodies, has formed the therapeutic landscape of quite a few different cancer types. In spite of the great clinical results produced by some inhibitors in some cases, most cancer patients still present de novo or adaptive resistance, and thus, the overall efficacy of this type of immunotherapy is not sufficient. Here, we explore emerging immune checkpoint molecules apart from anti-PD-1/anti-PD-L1 and anti-CTLA-4, presently being used in the clinical setting as mono- or combinatorial therapy against various cancer types. Methods-Primary publications with results between January 2014 and December 2019 were investigated on PubMed. ClinicalTrials.gov was screened for finding phase I/II/III cancer trials on the use of new immune checkpoint targets, including LAG-3, TIM-3, TIGIT, and VISTA, which are active (recruiting or not) or completed. Results-We recapitulate the clinical data associated with these immune checkpoint inhibitors and analyze their application prospects. The investigation about such emerging molecules has produced encouraging outcomes in preclinical studies and/or clinical trials. Conclusions-Although monotherapy treatment has yielded impressive results in some cases, the current attempts emphasize more the design of combinatorial immune checkpoint inhibition that targets non-redundant pathways to achieve a synergistic effect against cancer cells. It seems that such new combinatorial checkpoint inhibition schemes will achieve better outcomes for the patients than the ones witnessed with CTLA-4 or PD-1/PD-L1 blockers.