Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

Abstract

In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing.

Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer

“…Whether aneuploidy-induced stress pathway inhibitors might synergize with Mps1 inhibitors remains to be determined. Chemotherapy, targeted therapies, and radiotherapy can promote tumor immunity by inducing immunogenic cell death (32,33). Combinations of these cancer therapies with immune-checkpoint inhibitors are being explored to achieve additive or synergistic clinical activity.…”

Inhibitors of the PD-1 Pathway in Tumor Therapy

“…Most tumors require combination therapies for optimal clinical efficacy, and PD-1 has become a foundational building block for combination therapies primarily at the priming and effector steps (8, 49, 50). In animal models, enhancing T cell priming using combinations with TLR ligands such as CpG, vaccines such as GVAX, or oncolytic viruses have shown additive or synergistic effects with PD-1 blockade.…”

Future cancer research priorities in the USA: a Lancet Oncology Commission

“…For non-responding cancers and patients, other clinical applications under investigation include targeting other immune regulatory pathways (eg, CD137, OX40, GITR, TIGIT, and LAG-3) and the use of oncolytic viruses and targeted therapies to promote immunogenic death. 131,132 The use of PD-1 or PD-L1 immune checkpoint inhibitors has been helped by measurements of PD-L1 expression in tissue from several tumour types, although the correlation between expression and clinical response remains dubious. Emerging data also suggest that tumour mutational burden 133 or microsatellite instability 44 could provide additional refinements in identifying tumours that will respond to these drugs.…”