Advances on immune-related adverse events associated with immune checkpoint inhibitors

doi:10.1007/s11684-019-0735-3

Front. Med.

2021, Vol. 15

Issue (1) : 33-42 https://doi.org/10.1007/s11684-019-0735-3

REVIEW

Advances on immune-related adverse events associated with immune checkpoint inhibitors

Yong Fan¹, Yan Geng¹, Lin Shen², Zhuoli Zhang¹(

)

¹. Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing 100034, China
². Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China

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Abstract

Immunotherapy has recently led to a paradigm shift in cancer therapy, in which immune checkpoint inhibitors (ICIs) are the most successful agents approved for multiple advanced malignancies. However, given the nature of the non-specific activation of effector T cells, ICIs are remarkably associated with a substantial risk of immune-related adverse events (irAEs) in almost all organs or systems. Up to 90% of patients who received ICIs combination therapy experienced irAEs, of which majority were low-grade toxicity. Cytotoxic lymphocyte antigen-4 and programmed cell death protein-1/programmed cell death ligand 1 inhibitors usually display distinct features of irAEs. In this review, the mechanisms of action of ICIs and how they may cause irAEs are described. Some unsolved challenges, however really engrossing issues, such as the association between irAEs and cancer treatment response, tumor response to irAEs therapy, and ICIs in challenging populations, are comprehensively summarized.

Keywords cancer immunotherapy immune checkpoint inhibitors immune-related adverse events review

Corresponding Author(s): Zhuoli Zhang

Just Accepted Date: 05 May 2020 Online First Date: 11 August 2020 Issue Date: 11 February 2021

Cite this article:

Yong Fan,Yan Geng,Lin Shen, et al. Advances on immune-related adverse events associated with immune checkpoint inhibitors[J]. Front. Med., 2021, 15(1): 33-42.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0735-3
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I1/33

Fig.1 Schematic of ICIs in cancer therapy. (A) Normal T cell activation requires two signals to become fully activated. The primary signal (signal 1) occurs when the MHC that is presented by the APC binds to the TCR. However, signal 1 by itself is insufficient to enable T cell activation. A second signal (signal 2) occurs when a costimulator called CD28 binds to B7 (CD80 and CD86) on the surface of the APC. Following this interaction, T cells are activated and perform various effector functions (e.g., killing of tumor cells). (B) Several inhibitory molecules in T cells, named immune checkpoints, function to maintain a balance of immunity. CTLA-4 was the first described immune checkpoint that was expressed on T cell surface only after T cell activation. However, CTLA-4 has high homology to CD28 and binds to B7 molecules with much higher affinity than CD28, inhibiting T cell activation. PD-1 is another negative regulatory receptor expressed on the T cell surface that generally binds to either PD-L1 (expressed widely in multiple tissues and tumor cells) or PD-L2 (restricted to professional APCs). Under pathological conditions, the over-activation of both CTLA-4 and PD-1/PD-L1 pathways can suppress the activation of T cells and result in the exhaustion of immune response. (C) Blocking CTLA-4 and PD-1/PD-L1 inhibitory signal pathways by using specific antibodies (known as ICIs) diminishes the threshold for T cell activation and boosts anti-tumor activity by re-invigorated T cells but may also cause immune-related adverse events.

Tab.1 Overview of ICIs approved by the FDA (until April 2019)

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