Predictive biomarkers for checkpoint inhibitor-based immunotherapy

Abstract

The clinical development of checkpoint inhibitor-based immunotherapy has ushered in an exciting era of anticancer therapy. Durable responses can be seen in patients with melanoma and other malignancies. Although monotherapy with PD-1 or PD-L1 agents are typically well tolerated, the risk of immune-related adverse events increases with combination regimens. The development of predictive biomarkers is needed to optimise patient benefit, minimise risk of toxicities, and guide combination approaches. The greatest focus has been on tumour-cell PD-L1 expression. Although PD-L1 positivity enriches for populations with clinical benefit, PD-L1 testing alone is insufficient for patient selection in most malignancies. In this Review, we discuss the status of PD-L1 testing and explore emerging data on new biomarker strategies with tumour-infiltrating lymphocytes, mutational burden, immune gene signatures, and multiplex immunohistochemistry. Future development of an effective predictive biomarker for checkpoint inhibitor-based immunotherapy will integrate multiple approaches for optimal characterisation of the immune tumour microenvironment.

Conflict of interest statement

Declaration of interests

GTG reports personal fees from Novartis and Merck. LMW reports personal fees from Merck, Genentech, Jounce Pharmaceuticals, Celldex Pharmaceuticals, and Merrimack Pharmaceuticals. MBA reports personal fees from Bristol-Myers Squibb, Merck, Genentech/Roche, Novartis, Pfizer, and Astra Zeneca.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure. Immune response in the tumour microenvironment

After an immune response directed against tumour cells, immune tolerance can develop in the tumour microenvironment. Various mechanisms have been described including upregulation of tumour cell PD-L1 and dendritic cell and macrophage IDO expression in response to interferon γ signalling, upregulation of additional checkpoints (eg, LAG3), and enhanced regulatory T-cell function. These events serve both as potential therapeutic targets and predictive biomarkers. MHC I=major histocompatibility complex I.