Abstract
Immune checkpoint inhibitors (ICIs) are a class of drug that produces durable and sustained anti-tumour responses in a wide variety of malignancies. The exponential rise in their use has been mirrored by a rise in immune-related adverse events (IrAEs). Knowledge of such toxicities, as well as effective management algorithms for these toxicities, is essential to optimize clinical efficacy and safety. Currently, the guidelines for management of the IrAEs are based largely on retrospective studies and case series. In this article, we review the current landscape of clinical trials investigating the management of IrAEs with an aim to develop standardised, randomised controlled trial-based management algorithms for ICI-related toxicities.
Introduction
Cancer immunotherapy is based on the principle that a patient’s own immune system can be harnessed to reject a malignant tumour. The concept of immunoediting, which holds that many early cancers are eliminated by immune surveillance, is supported by experiments with immunodeficient mice and epidemiologic studies of immunocompromised individuals [1]. Cancer cells must become less immunogenic or disable immunologic components to survive and spread throughout the body. There are numerous cancer immunotherapy techniques that are currently being used in the clinic or under development, such as cytokines, cellular therapies, viral vectors for gene transfer, and antibody-based therapies [2]. Collectively, these therapeutic modalities represent a paradigm shift in cancer treatment by targeting key pathways and cell types within the host immune response, rather than the cancer cell, and have been successful in improving clinical outcomes for patients with both solid tumour and haematologic malignancies [3,4,5,6].
Mechanisms of Immune-Related Toxicity
Immune-related adverse events may be mediated by different mechanisms, including T-cells, autoantibodies, cytokines, HLA-predisposition, and the microbiome [28]. It is known that increasing T-cell activity against antigens that are present in tumour and healthy tissue, increasing levels of existing antibodies, increasing levels of inflammatory cytokines, and enhancing complement-mediated inflammation result in toxicity. Different checkpoint inhibitors also affect tissues in different manners, to different degrees; for example, patients treated with anti-CTLA-4 therapy or anti-PD-1 therapy experience differences in organ-specific toxicities.
Management of IrAEs
Immune-related adverse events result from host immune response directed against normal organs. As a result, the mainstay of treatment in the acute setting is immunosuppression with oral corticosteroids, high-dose steroid therapy, or additional immunosuppressants in more severe or refractory cases [34]. For steroid-refractory cases, early initiation of additional immunosuppressants or plasmapheresis can be considered. This is often under the close guidance of disease-specific subspecialists [34]. Examples of immunomodulatory agents that may be used for IrAE management include infliximab, tumour necrosis factor inhibitors (TNFi’s), mycophenolate mofetil, anti-thymocyte globulin (ATG), calcineurin inhibitors, methotrexate, or intravenous gamma-globulin (IVIG) [34]. The management of immunotherapy toxicities is guided by Common Terminology Criteria for Adverse Events (CTCAE–Version 5.0) grade of severity [35], type, and number of adverse events [25,26,27].
Clinical Trials in IrAEs
In addition to their use in comparing novel immunotherapy treatments to the current standard of care, clinical trials have been developed and initiated to understand aspects of the safety of ICIs, including the natural history of IrAEs and the safety and efficacy of ICIs in high-risk populations, including those with pre-existing autoimmune disease and solid organ transplant [44,45,46].
Discussion
The discovery of immune checkpoint proteins represents a significant breakthrough in the field of cancer immunotherapy. However, not all patients respond favourably to these drugs, and many develop IrAEs. IrAEs range in severity from mild to severe and can often be life-threating, resulting in death. In cases of moderate to severe toxicity, the ICI, which may be providing measurable clinical benefit, is often withheld. The standard treatment of such IrAEs is with corticosteroids, either orally or intravenously, with limited evidence for alternative immunosuppressive agents, including infliximab, cyclophosphamide, mycophenolate, and intravenous immunoglobulin. The evidence for the use of these agents comes primarily from case study series, retrospective studies, and personal experience of the treating physician. The gold standard test to examine the safety and efficacy of these agents is the prospective double-blind, randomised, interventional clinical trial, and a number of these have been initiated over recent years for various agents and various IrAEs.
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