Elsevier

European Journal of Cancer

Volume 54, February 2016, Pages 139-148
European Journal of Cancer

Review
Immune-related adverse events with immune checkpoint blockade: a comprehensive review

https://doi.org/10.1016/j.ejca.2015.11.016Get rights and content

Highlights

  • Programmed cell death protein-1 and cytotoxic T-lymphocyte-associated antigen-4 have roles in self-tolerance and various auto-immune conditions.

  • Tumour neoantigens and normal tissue antigens could be cross-reactive.

  • A correlation between dysimmune toxicity and antitumoural efficacy is emerging.

  • Steroids must be used with caution in routine practice to treat dysimmune toxicity.

Abstract

Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines.

Introduction

For over 50 years now, surgery, radiotherapy and chemotherapy have been the physician's main weapons against cancer. However, cancer mortality rates remain high. Recently, immunotherapy has become a new way of overcoming cancer [1]. Cancer cells are able to turn immunosuppressive molecules to their advantage by inhibiting antitumour lymphocytes and thus escaping destruction by the immune system. In the tumour microenvironment, immunosuppressive molecules such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1 are markedly overexpressed [1]. Targeting these molecules, the immune checkpoint blockade agents reactivate cytotoxic T cells to destroy tumour cells. The first immune checkpoint blockade to display high antitumour activity was the anti-CTLA-4 monoclonal antibody ipilimumab [2]. Since then, the anti-PD-1 antibodies nivolumab and pembrolizumab have demonstrated high activity in melanoma [3], [4] and subsequently many other types of cancer – prompting a ‘PDLoma’ of activity (Fig. 1).

By unbalancing the immune system, immune checkpoint blockade favours the development of autoimmune manifestations [5], [6] also referred to as immune-related adverse events (IRAEs). Most of these adverse events can be managed by counteracting lymphocyte activation with steroids [7]. Although the use of steroids causes the IRAEs to regress, the associated immunosuppression may compromise the antitumour response [7]. Understanding IRAEs is critical for their early detection and appropriate management.

Section snippets

The physiological roles of CTLA-4 and PD-1/PD-L1.

Self-tolerance in humans is partly maintained by the inhibition of auto-reactive T-cells through the CTLA-4 and PD-1/PD-L1 axes [8], [9]. Polymorphisms of PD-1 and CTLA-4 are associated with various autoimmune conditions summarised in Table 1. Interestingly, some of these autoimmune diseases share clinical features with the IRAEs that emerge with immune checkpoint blockade agents.

Terminology used to report toxicity in clinical trials

The use of harmonised terminologies to report and describe IRAEs is a major issue. Several verbatim (reported) terms for IRAE are used, such as ‘drug-related adverse event’ or ‘event of special interest’. As much as possible, a single terminology as IRAE would enable more understandable, accurate interpretation of the safety data.

Furthermore, the quality of IRAE data reporting in clinical trials appears to be suboptimal [10], and important data such as the event's time of onset, reversibility,

Biomarkers-efficacy relationship

The first-reported biomarker for predicting the efficacy of anti-PD-1 therapy was the expression level of PD-L1 on tumour cells [11]. However, there is still no consensus on how a PD-L1-positive tumour should be defined, since each pharmaceutical company has used different antibodies clones for its immunohistochemically staining, different scoring algorithms (cancer cells alone versus cancer cells plus associated infiltrating immune cells), and different positivity thresholds. Other biomarkers

Frequency and timeline of occurrence

IRAEs are frequent; they occur in up to 90% of patients treated with an anti-CTLA-4 antibody [2] and 70% of patients treated with an PD-1/PD-L1 antibody [11], [17]. By comparing the various organs involved, grade I–II events mainly affect the skin and the gut, whereas grades III–V are mainly restricted to the digestive tract (Fig. 2). Most IRAEs occur within 3–6 months of the initiation of anti-CTLA-4 [18], [19] or anti-PD-1 [7]. While the IRAE risk appears to be dose-dependent with anti-CTLA-4

Understand IRAEs organ by organ

The clinical spectrum of IRAEs is portrayed in the Fig. 3.

Further perspectives to explore IRAEs

Although the immune checkpoint blockade is typically described as being well-tolerated, they still generate life-disabling IRAEs that are sometimes severe and/or irreversible. The long-term impact of immune checkpoint blockade on quality of life should be specifically evaluated in future research. Furthermore, the potential detrimental effect of steroid administration (in response to an IRAE) on anticancer efficacy has yet to be investigated. Further biological and ancillary pharmacogenomics

Conclusion

Immune checkpoint blockade leads to a new spectrum of dysimmune toxicity in hemato-oncology. From a practical perspective, the management requires a close collaboration between with organ specialists, which could see in return new insights into the pathophysiology of autoimmune diseases such as Crohn's disease and hypophysitis. Dysimmune toxicity may be associated with the antitumour response and the use of steroids must be cautious. Dysimmune toxicity need to be extensively explored in the way

Conflict of interest statement

None declared for all authors.

Acknowledgements

The authors thank Nelly Hainault for managing the review process and David Fraser for language assistance.

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