Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune‐modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

The immune system has developed a complex series of mechanisms to detect and eradicate cancer cells. These pathways protect against the development of malignancy but can promote the selection of tumor cells, which are equipped to avoid the host's immune response. The concept of cancer immunoediting, which highlights the dual role of the immune system in protecting against tumor growth while also shaping tumor immunogenicity, describes the process of tumor development using 3 steps: elimination, equilibrium, and escape.1 During the elimination phase, the host's innate and adaptive immune systems recognize and respond to tumor‐specific antigens. Some tumor cells survive elimination and enter the equilibrium phase, during which the adaptive immune system prevents outright tumor growth but exerts a selective pressure on the remaining malignant clones. Tumor cells escape when they develop resistance to the antitumor immune response. Multiple mechanisms have been described to account for the evolution of this escape, including alteration or loss of antigens, manipulation of cytokine expression, and upregulation of immune checkpoint proteins.

Cancer immunotherapies, which were developed based on studies of the mechanisms of tumor escape, manipulate the immune system to reactivate the antitumor immune response and overcome the pathways leading to escape. Early approaches to cancer immunotherapy targeted cytokines to affect immune cell function. For example, high‐dose interleukin 2 (IL‐2) and interferon (IFN) α‐2b lead to multiple downstream effects4 and have been used to treat advanced melanoma and renal cell carcinoma (RCC).5 Therapeutic approaches to manipulate multiple aspects of the immune system have subsequently been investigated, including immune checkpoint inhibitors (ICIs), adoptive cell therapy, oncolytic viruses, and cancer vaccines.

Immunotherapies have transformed the treatment landscape for multiple solid and hematologic malignancies but confer unique toxicity profiles, which vary depending on the type of immunotherapy and are related to the specific mechanism of action. Cytokines, such as high‐dose IL‐2, lead to multiple downstream effects on T cells and natural killer (NK) cells, which, in turn, cause capillary leakage and a sepsis‐like syndrome. In severe cases, this can result in multiorgan failure, which has historically limited the clinical utility of cytokine therapy.6 ICIs, including antibodies against cytotoxic T lymphocyte antigen‐4 (CTLA‐4) and programmed cell death protein 1 (PD‐1) and its ligand PD‐L1, disinhibit T‐cell antitumor function, which can lead to a distinct constellation of organ‐specific inflammatory side effects, or irAEs.5 Another approach to immunotherapy is the ex vivo modification of patient T cells to generate specific antitumor reactivity, a process termed adoptive cell therapy.7 For instance, chimeric antigen receptor (CAR) T cells, which are engineered to recognize a tumor‐associated antigen, are used to treat hematologic malignancies and are being investigated in multiple solid tumor types.7 The most common CAR‐T toxicities in hematologic malignancies are cytokine release syndrome (CRS) and ICANS.8 Because of these toxicity profiles, treatment with cancer immunotherapies requires close monitoring, and toxicity often requires specific management, which can include steroids or immune‐modulating agents.5 As the use of immunotherapy in cancer continues to expand, guidelines addressing the management of ICI and CAR‐T toxicity have also been developed.

In this review, we discuss the pathophysiology, presentation, diagnosis, and management of toxicities associated with cancer immunotherapies.
 

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Managing editor          
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Toxicology: Open Access