Immune Checkpoint Protein Inhibition for Cancer: Preclinical Justification for CTLA-4 and PD-1 Blockade and New Combinations

Abstract

Over the last two decades, our understanding of the molecular basis of immunity has revealed the complexity of regulatory pathways involved in immune responses to cancer. A significant body of data support the critical importance of immune checkpoints in the control of the adaptive immune response to malignancy, and suggest that inhibitors of those checkpoints might have significant utility in treating cancer. This has been borne out by the recent US Food and Drug Administration (FDA) approvals of two different antibodies, one against cytotoxic T-lymphocyte antigen-4 (CTLA-4) and one against programmed death-1 (PD-1). Here, we provide a comprehensive review of the literature regarding the preclinical justification for the use of CTLA-4 and PD-1 blockade as monotherapy, and as combination therapy in the treatment of cancer. The animal data strongly supported the use of these drugs in patients, and in many cases suggested strategies that directly led to successful registration trials. In contrast, many of the toxicities, and some of the unusual response patterns seen in patients with these drugs, were not predicted by the preclinical work that we cite, highlighting the importance of early-phase trials with patients to inform future drug development. In addition, we review herein the preclinical data surrounding emerging immune checkpoint proteins, including BTLA, VISTA, CD160, LAG3, TIM3, and CD244 as potential targets for inhibition. The current comprehensive review of the literature regarding CTLA-4 and PD-1, as well as a number of novel checkpoint proteins demonstrates a strong preclinical basis for the use of these antibodies singly and in combination to overcome checkpoint inhibition in the treatment of cancer. We also suggest that the use of these antibodies may augment the efficacy of other activating immune antibodies, cytokines, radiation, and adoptive cell therapy in human cancer.