PrIMEr

Immune-​related adverse events of checkpoint inhibitors

Manuel Ramos-Casals​ 1,2,3 ✉ , Julie R. Brahmer4, Margaret K. Callahan5,6,7, Alejandra Flores-Chávez​ 2, Niamh Keegan5, Munther A. Khamashta8, Olivier Lambotte9,10, Xavier Mariette11, Aleix Prat12,13 and Maria E. Suárez-​Almazor14 Abstract | Cancer immunotherapies have changed the landscape of cancer treatment during the past few decades. Among them, immune checkpoint inhibitors, which target PD-1, PD-L1​ and CTLA-4, are increasingly used for certain cancers; however, this increased use has resulted in increased reports of immune-​related adverse events (irAEs). These irAEs are unique and are different to those of traditional cancer therapies, and typically have a delayed onset and prolonged duration. IrAEs can involve any organ or system. These effects are frequently low grade and are treatable and reversible; however, some adverse effects can be severe and lead to permanent disorders. Management is primarily based on corticosteroids and other immunomodulatory agents, which should be prescribed carefully to reduce the potential of short-term​ and long-term​ complications. Thoughtful management of irAEs is important in optimizing quality of life and long-term​ outcomes.

Cancer immunotherapies are broadly defined as thera- that is not dependent on individual cancer-​specific anti- pies that directly or indirectly target any component of gens2. The use of ICIs for cancer therapy is increasing; the immune system that is involved in the anti-​cancer however, a key challenge that has emerged with the immune response, including the stimulation, enhance- progressive implementation of ICIs in clinical practice ment, suppression or desensitization of the immune sys- is their uncontrolled collateral effects on the immune tem. These therapies comprise different approaches that system that can lead to so-​called immune-​related include the use of specific drugs (monoclonal antibodies, adverse events (irAEs)3. ICIs have a different spectrum small proteins or fusion proteins) that target proteins on of toxicities than standard chemotherapy or other bio- the surface of cancer cells or immune cells, and other ther- logical agents, and most toxicities result from excessive apies, such as cytokines, oncolytic virus therapies, cancer immunity against normal organs3 (Box 2). vaccines or cell-​based therapies (such as adoptive T cell Owing to the increased use of ICIs for cancer treat- transfer and chimeric antigen receptor T cell therapies)1. ment, the cumulated annual number of irAEs is increas- One class of these therapies — immune checkpoint ing exponentially, with nearly 13,000 cases reported in inhibitors (ICIs) — serves to induce an anti-​tumour 2018 (ref.4). More than two-thirds​ of reported cases of can- immune response by blocking immune checkpoints. cer immunotherapy-related​ irAEs are related to ICIs, and Normally, immune checkpoints, key examples of which three drugs (ipilimumab, nivolumab and pembrolizumab) include CTLA-4 and PD-1 pathways, downregulate T cell are responsible for almost 60% of reported cases4. responses and act to protect the body from possibly dam- This Primer provides an update on ICI-​associated aging immune responses, such as autoimmune disease irAEs (subsequently referred to as irAEs) from a (Fig. 1). However, tumours can hijack this system to evade multi-disciplinary​ perspective. Owing to their increased the immune system through the activation of immune prevalence and potentially severe nature, this Primer checkpoints and inhibition of the T cell response. Thus, focuses on the adverse effects of ICIs only, rather than interfering with these immune checkpoint pathways can other types of cancer immunotherapy. induce an anti-​tumour immune response and convey therapeutic benefits in patients with cancer. Epidemiology Several ICIs are approved for the treatment of vari- Frequency of irAEs ous cancer types (Box 1). These drugs are all monoclonal Adverse events in clinical trials are reported and graded ✉e-mail:​ [email protected] antibodies that target either CTLA-4 signalling or PD-1 using the Common Terminology Criteria for Adverse https://doi.org/10.1038/ signalling (by targeting PD-1 or the PD-1 ligand PD-L1),​ Events (CTCAE) from the US National Cancer Institute. s41572-020-0160-6 and they have a universal effect on immune responses The CTCAE ranges from grade 1 to grade 5, which refers

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Author addresses (OR 6.5, 95% CI 3.0–14.3) and rash (OR 2.0, 95% CI 1.8–2.3) were more common with CTLA-4 inhibitors, 1Department of Autoimmune Diseases, ICMiD, Barcelona, Spain. whereas pneumonitis (OR 6.4, 95% CI 3.2–12.7), hypo- 2 Laboratory of Autoimmune Diseases Josep Font, IDIBAPS-​CELLEX, Barcelona, Spain. thyroidism (OR 4.3, 95% CI 2.9–6.3), arthralgia (OR 3.5, 3Department of Medicine, University of Barcelona, Hospital Clínic, Barcelona, Spain. 4 95% CI 2.6–4.8) and vitiligo (OR 3.5, 95% CI 2.3–5.3) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns 14 Hopkins, Baltimore, MD, USA. were more common with PD-1 inhibitors . The precise 5Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan biological explanations for the differences in irAE local- Kettering Cancer Center, New York, NY, USA. ization and severity with different ICIs are not entirely 6Weill Cornell Medical College, New York, NY, USA. known. Theoretically, CTLA-4 blockade might induce 7Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, a greater magnitude of T cell proliferation or reduced + + New York, NY, USA. CD4 CD25 regulatory T (Treg) cell-mediated​ immuno- 8Lupus Clinic, Rheumatology Department, Dubai Hospital, Dubai, UAE. suppression, and PD-1 blockade might activate a smaller 9APHP Médecine Interne/Immunologie Clinique, Hôpital Bicêtre, Paris, France. number of T cell clones15,16 (although most circulating 10 Université Paris-Saclay,​ INSERM U1184, CEA, Immunology of Viral Infections T cells do not express PD-1, they can be induced to do and Autoimmune Diseases, IDMIT Department, IBFJ, Fontenay-​aux-Roses​ and so on stimulation during T cell receptor-​dependent Le Kremlin-Bicêtre,​ Paris, France. 15 11Université Paris-Saclay,​ INSERM, CEA, Centre de recherche en Immunologie des signalling) (see Mechanisms/pathophysiology below). infections virales et des maladies auto-immunes;​ AP-HP.​ Université Paris-Saclay,​ Few data are available about the potential differences Hôpital Bicêtre, Rheumatology Department, Le Kremlin Bicêtre, Paris, France. in irAEs owing to the specific pharmaco-immunological​ 12Translational Genomic and Targeted Therapeutics in Solid Tumors, Institut composition of ICIs. However, some studies have d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. demonstrated that antigenic effects of immunothera- 13Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain. pies can result in the development of neutralizing anti- 14Section of Rheumatology/Clinical Immunology, The University of Texas MD Anderson bodies and may depend on the degree of ‘humanization’ Cancer Center, Houston, TX, USA. of the therapy17. Indeed, the formation of antibodies to biological agents is quite common, although these to mild, moderate, severe, life-​threatening or death, in antibodies seem to have primarily neutralizing effects ascending order5. The general safety of ICIs has been that decrease therapeutic efficacy and cause allergic or estimated in a meta-​analysis of 36 phase II/III trials, hypersensitivity reactions18. The immunogenicity of ICIs showing a pooled incidence ranging between 54% and has been assessed in a few studies. In six clinical stud- 76% for all adverse events6. ies with nivolumab, anti-​drug antibodies were found at IrAEs can occur in any organ system, with the least once in 12.7% of patients and persistently (detected median onset usually within 2–16 weeks from the com- in at least two consecutive samples, separated at least mencement of therapy, depending on the organ system 16 weeks apart) in only 0.3% of patients without any clini- involved7. However, onset of irAEs has been described cal consequence (lack of association with hyper­sensitivity, within a few days of ICI initiation, and ≥1 year after infusion reactions or loss of efficacy)19, whereas the completion of therapy8,9. The risk of first-​onset irAEs maximum anti-​drug antibody-​positive rates were is threefold higher during the first 4 weeks of treatment 54.1% for atezolizumab, 5.9% for durvalumab, 2.9% for than between 4 weeks and the end of treatment10. As avelumab and 2.1% for pembrolizumab20. Although the T cell autoreactive clones that underlie these irAEs the clinical implications of anti-​ICI antibodies remain are presumably present long after the cessation of treat- to be elucidated, these effects seem to primarily affect ment, it is possible that irAEs may present many years treatment efficacy rather than cause adverse events20. after treatment. Early toxicity (that is, between 1 and 12 weeks after treatment initiation) is most commonly Combination strategies seen as dermatological effects for both CTLA-4 and The increasing use of combination strategies (com- PD-1 inhibitors11. Among individual ICIs, data from bining immunotherapies with traditional cancer treat- one meta-analysis​ showed that the most common irAEs ments, such as chemotherapy, or combining two types for ipilimumab are dermatological, gastrointestinal and of immunotherapy) might improve the efficacy of cancer renal toxicities, for pembrolizumab they are arthralgia, immunotherapy but could also amplify irAEs2. pneumonitis and hepatic toxicities, for nivolumab they With respect to the development of unexpected tox- are endocrine toxicities, and for atezolizumab they are icities, combining chemotherapies with PD-1 inhibitors hypothyroidism6. is not characterized by additional irAEs, and reported adverse effects are consistent with those of each Pharmacological class-specific​ irAEs agent21,22. Similarly, combining CTLA-4 inhibitors with Consistent with the distinct functions of immune check- PD-1 or PD-​L1 inhibitors did not lead to unexpected points, the types of irAEs related to single-​drug ther- new irAEs15,16. However, the frequency of adverse events apy targeting the CTLA-4 or PD-1 pathways differ12. with combinatorial therapy is higher than with mono- Typically, PD-1 and PD-L1​ inhibitors are better tolerated therapy8. Indeed, in one study, the overall prevalence of than CTLA-4 inhibitors13; indeed, grades 3 and 4 irAEs irAEs (>90%) and severity (with grade ≥3 adverse events were more common with CTLA-4 inhibitors than PD-1 representing ~60% of the total irAEs) when combining inhibitors in one systematic review14. In this review, CTLA-4 inhibitors with PD-1 or PD-​L1 inhibitors was grade 3 or grade 4 irAEs comprised 31% of all irAEs higher than with monotherapy16. for CTLA-4 inhibitors and 10% for PD-1 inhibitors; In addition, the phenotype of organ-​specific irAEs of note, colitis (OR 8.7, 95% CI 5.8–12.9), hypophysitis can be modified with combination therapies. One study

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a b some cancers. For example, comparison of irAEs owing Antigen- to PD-1 inhibitors in melanoma, non-​small-​cell lung presenting cell Tumour cell cancer and renal cell carcinoma showed that patients with melanoma had a higher frequency of dermatologi- cal (particularly vitiligo) and gastrointestinal irAEs and a lower frequency of pneumonitis than patients with other cancers14. PD-L1 Risk factors Anti-PD-L1 Anti-CTLA-4 The frequency of irAEs varies widely according to the CD80 or MHC antibody antibody CD86 class II Anti-PD-1 ICI used and the organ-​specific damage triggered, sug- CD28 CTLA-4 antibody gesting that there is a specific population of individuals TCR PD-1 who are prone to developing irAEs, maybe involving an unknown genetic background11. In addition, there are substantial individual variations in the risks of irAEs, as some patients do not develop adverse events after ↑ T cell months of therapy, whereas others have life-threatening​ T cell ↑ T cell activation irAEs after a single infusion. activation One explanation for the difference in the risk of irAEs ↑ T cell apoptosis could be that some individuals have a predisposition to autoimmunity. To this end, some studies have reported that ~10% of individuals who developed rheumatic irAEs had a family history of autoimmune disorders, | Fig. 1 Mechanism of immune checkpoints and immune checkpoint inhibitors. and ~25% of individuals had a personal history of auto­ The main immunotherapy approaches that are approved for clinical use in cancer are the 24–27 immune checkpoint inhibitors. These therapies are monoclonal antibodies that target immune disorders . Furthermore, a number of the CTLA-4 and PD-1 receptors and the PD-1 ligand PD-L1,​ which are involved in the CTLA4 and PDCD1 (encoding PD-1) polymorphisms 28,29 regulation of T cell activation. a | T cell activation requires two signals: first, antigen have been associated with autoimmune disorders . recognition by the T cell receptor (TCR) following antigen presentation by major Genetic variations could have a role in the risk of irAEs, histocompatibility complex (MHC) class II molecules on the surface of antigen-presenting​ although no clear evidence of strong genetic associations cells; and, second, signal modulation by CD80 or CD86 binding to the CD28 receptor. has been demonstrated. CTLA-4 is located on the T cell surface and competes with the CD28 receptor to bind Several studies have reported personal risk factors CD80 or CD86, thereby blocking T cell activation. CTLA-4 inhibitors block CTLA-4–CD80 linked to the development of irAEs, such as a history of or CTLA-4–CD86 binding to facilitate T cell activation (dashed line). b | PD-1 is a surface autoimmune disease, use of CTLA-4 inhibitors and poor receptor that is expressed by T cells and promotes apoptosis of antigen-specific​ T cells kidney function of grade ≥330. In addition, one study has and reduces apoptosis of regulatory T cells253,254 through its interaction with its ligand, linked an increased body mass index with a higher risk PD-L1,​ which is expressed by tumour cells and myeloid cells. This interaction is useful 31 in preventing autoimmunity in physiological conditions, but cancer cells exploit this of irAEs in patients treated with pembrolizumab , but process to escape from immune system activity upregulating PD-L1​ expression255,256. this association was not confirmed in patients treated PD-1 and PD-L1​ inhibitors block the PD-1–PD-L1​ interaction, facilitating T cell activation with atezolizumab32 or ipilimumab33. By comparison, and survival (dashed lines). female sex and corticosteroid use were identified as pro- tective markers against the development of irAEs in one study of 78 patients treated with ipilimumab, nivolumab of 30 patients with clinically confirmed arthritis demon- or pembrolizumab30. All these data require replication strated that individuals treated with combination ICI before firm conclusions regarding these associations therapy were more likely to present with knee arthritis, can be drawn. Age has not been associated with a to have higher levels of C-​reactive protein, to have a pre- differentiated toxicity profile in patients treated with vious irAE, and to have a reactive arthritis-like​ pheno­ ICI monotherapy34,35 and tolerance in elderly patients type than those treated with ICI monotherapy, who seems similar to younger people34. Whether other epi- were more likely to have initial small joint involvement demiological features, such as a patient’s ethnicity, are and arthritis as their only irAE23. Moreover, combina- associated with the risk of irAEs is unknown. tion therapy was associated with greater risk and earlier onset of irAEs, with up to fivefold shorter median time Mechanisms/pathophysiology to onset than monotherapy (32 days for combination CTLA-4 and PD-1 or PD-​L1 inhibitors result in therapy versus 146 days for monotherapy)10. non-​specific upregulation of immune pathways. Although there are commonalities between the immune Tumour-specific​ patterns of irAEs toxicity profiles of these therapies, there are important Overall, the types of irAEs do not seem to be specific differences in the frequency and clinical presentation of to the type of cancer12. Although cross-​study compari- specific irAEs and the most frequently affected organs14. sons should be interpreted with caution, some data sug- These phenotypic variations suggest that the mecha- gest that the frequency of specific irAEs varies between nisms of irAEs differ between ICIs, although the precise individuals with different cancers who receive the same mechanisms remain to be elucidated. Both CTLA-4 and ICI, suggesting that different organ-​specific immune PD-1 inhibition increases T cell activation and prolifer-

microenvironments could drive specific irAE patterns in ation, abrogates Treg cell functions, and possibly boosts

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Box 1 | Approved immune checkpoint inhibitors according to cancer type of effector T cells to Treg cells in the tumour microen­ vironment40, possibly enhancing anti-tumour​ responses Anti-​CTLA-4 antibodies -- Merkel cell carcinoma and contributing to the therapeutic benefit observed • Ipilimumab -- Metastatic solid tumours classified with CTLA-4 inhibitors40. In accordance with these -- Colorectal cancera as microsatellite instability high or animal data, the numbers of circulating T cells are -- Melanoma deficient mismatch repair reg -- Renal cell carcinomaa -- Non-small-​ cell​ lung cancer decreased in patients receiving ipilimumab with no -- Primary mediastinal large B cell significant changes in the relative frequencies of naive, Anti-​PD-1 antibodies 41 lymphoma central memory and effector memory cells , although • Nivolumab -- Stomach cancer not all studies confirmed this reduction42. An imbalance -- Bladder cancer -- Colorectal cancer • Cemiplimab in Treg cells and type 17 T helper (TH17) cells could con- 43 -- Head and neck cancer -- Cutaneous squamous cell carcinoma tribute to irAEs associated with ICIs . Enhanced TH17 cell responses have prominent roles in the pathogenesis -- Hepatocellular carcinoma Anti-​PD-​L1 antibodies -- Hodgkin lymphoma • Atezolizumab of many autoimmune diseases including rheumatoid -- Melanoma -- Bladder cancer arthritis, psoriatic arthritis and inflammatory bowel 44 -- Non-small-​ cell​ lung cancer -- Breast cancer disease owing to the production of proinflammatory -- Renal cell carcinoma -- Non-small-​ cell​ lung cancer cytokines such as IL-17A, IL-21 and IL-22 by these cells. • Pembrolizumab • Avelumab Indeed, CTLA-4 inhibitors increase the numbers of cir- -- Bladder cancer -- Bladder cancer culating TH17 cells in patients with melanoma, especially -- Cervical cancer -- Merkel cell carcinoma in those who developed irAEs45, and increased IL-17 --Gastro-oesophageal​ junction • Durvalumab levels have been associated with severe irAE, particu- cancers -- Bladder cancer larly colitis, in patients receiving ipilimumab, suggesting -- Head and neck cancer -- Non-small-​ cell​ lung cancer -- Hepatocellular carcinoma that the effect of ICIs on TH17 cells contributes to the 46 -- Hodgkin lymphoma aIn combination with nivolumab. manifestations of irAEs . PD-1 inhibition also enhances T cell activation, but results in different phenotypes of irAEs than CTLA-4 inhibition. PD-1 is expressed on T cells, humoral autoimmunity36 (Fig. 2), although it is likely that whereas its ligands PD-​L1 and PD-​L2 are present on specific pathways are more prominent in one therapy antigen-​presenting cells, tumour cells and various nor- type versus the other, resulting in differences in irAE mal tissues, and normally act to downregulate T cell acti- phenotypes. vation47 (Fig. 1). Both PD-1 and PD-L1​ are expressed by

Treg cells, and this pathway appears to be involved in the 48,49 T cell activation differentiation of TH1 cells into Treg cells . Mice defi- Studies in animal models that lack immune checkpoints cient in PD-1 or PD-​L1 develop various autoimmune or in patients with genetic disorders that affect immune manifestations depending on their genetic backgrounds, checkpoints can be used to study the immunological which, in some cases, is mediated by autoantibodies (for consequence of immune checkpoint inhibition, and can example, anti-​troponin I antibodies in PD-1-​deficient shed some light on the mechanisms underlying irAEs. mice who develop cardiomyopathy)50–52. PD-1 and Ctla4-knockout​ mice develop profound and rapidly fatal PD-​L1 inhibition with monoclonal antibodies leads to

T cell lymphoproliferation, hypergammaglobulinae- a decrease in the number of circulating Treg cells that mia and T cell-​mediated autoimmunity37,38. Similarly, is associated with a more favourable progression-​free Ctla4fl/fl mice with acquired CTLA-4 deficiency during survival in patients treated for melanoma53. adulthood develop multi-​organ autoimmune disease, In addition to these cellular changes, both CTLA-4 although this disease is less severe than observed in those and PD-1/PD-L1​ inhibition result in increased cytokine with congenital deficiency37. In humans, two genetic production. Indeed, blocking CTLA-4 with mono­ diseases, CHAI (CTLA-4 haploinsufficiency with auto­ clonal antibodies in humans results in enhanced CD4+ immune infiltration) and LATAIE (LRBA deficiency with and CD8+ T cell activation, with subsequent release

autoantibodies, regulatory Treg cell defects, autoimmune of cytokines such as tumour necrosis factor (TNF), infiltration and enteropathy), which cause functional interferon-​γ (IFNγ) and IL-2 (refs15,54), which can lead abnormalities in CTLA-4 pathways have been described, to further T cell proliferation and activation. As dis- and result in widespread multi-organ​ lymphocytic infil- cussed above, IL-17 might mediate irAEs given both its 39 tration, Treg cell defects and autoantibody production . marked proinflammatory functions and the empirical Although the disease phenotypes in animal models and evidence showing increased circulating levels in individ- individuals with CTLA-4-​related genetic disorders are uals with some irAEs, such as colitis46. The role of other substantially more severe than irAEs in patients who proinflammatory cytokines is less evident, although receive CTLA-4 inhibitors, they all have similar types of there have been reports of increased IL-1RA, CXCL10 functional immune abnormalities. and TNF levels in patients with irAEs55. Anti-​TNF

Normally, Treg cells express CTLA-4 and downregulate agents have been successfully used to treat differ- immune responses by inhibiting effector T cell prolifer- ent irAEs in patients receiving ICIs, suggesting a role ation and cytokine release to maintain self-tolerance.​ In for this cytokine in the development of these adverse mice, administration of anti-CTLA-4​ antibodies impairs events56. However, the precise roles of these cytokines

Treg cell function and survival via antibody‐dependent in the development of irAEs are unknown and require cell‐mediated cytotoxicity, therefore increasing the ratio further study.

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Cross-reactivity​ tumoural antigenicity with melanoma, which is suggestive of cross-​reactivity Cross-​reactivity between anti-​tumour T cells and sim- between T cells against tumour antigen and melano- ilar antigens on healthy cells might underlie the devel- cytes11. In addition, cross-​reactivity has been suggested opment of some irAEs57, such as vitiligo in patients for ICI-​related myocarditis59 owing to low selectivity with melanoma treated with ICIs58. Data from the among the tumour-reactive​ T cell population and, there- ICIR-​BIOGEAS Registry revealed that, among 368 fore, cross-​reactivity with normal tissues8. In support of reported cases of vitiligo, 96% of cases were in patients this mechanism, post-​mortem tissue from two patients

Box 2 | Organ-based​ classification of immune-related​ adverse events in patients with cancer treated with immune checkpoint inhibitors Cardiac -- Autoimmune hepatitis -- Panuveitis • Myocarditisa -- Eosinophilic hepatitis -- Posterior uveitis -- Autoimmune myocarditis • Lymphocytic gastritis • Vogt–Koyanagi–Harada syndrome -- Myocardial fibrosis • Pancreatitis Pulmonary • Pericarditis Haematological • Interstitial lung diseasea -- Autoimmune pericarditis • Aplastic anaemia/pure red cell aplasia -- Alveolitis -- Pericardial effusion -- Organizative pneumonitis • Autoimmune haemolytic anaemia -- Pericardial tamponade -- Pneumonitis • Autoimmune neutropenia Dermatological -- Pulmonary fibrosis • Alopecia areata/universalis • Haemophagocytic lymphohistiocytosis -- Pulmonary haemorrhage • Dermatitis herpetiforme • Immune thrombocytopenic purpura Renal • Erythema multiforme Muscular • Acute tubulointerstitial nephritis/renal a tubular acidosis • Granuloma annulare • Myalgias a • Glomerulonephritis • Lichen planopilaris/planus/lichenoid • Myositis dermatitis -- Anti-synthetase​ syndrome Skeletal a • Panniculitis/erythema nodosum -- Bulbar myopathy • Arthralgia /polyarthralgia -- Dermatomyositis a • Pemphigoid/pemphigus • Arthritis -- Diaphragmatic lymphocytic polymyositis -- Monoarthritis • Psoriasis -- Necrotizing myopathy -- Oligoarthritis • Pyoderma gangrenosum -- Orbital myositis -- Polyarthritis • Sweet syndrome Neurological • Enthesitis a • Vitiligo • Aseptic meningitis • Fasciitis/eosinophilic fasciitis Endocrine • Encephalitis • Jaccoud arthropathy a • Adrenitis • Cranial nerve involvement • Polymyalgia rheumatica -- Adrenal insufficiency -- Bilateral hearing loss • Psoriatic arthritis -- Cortisol deficiency -- Facial palsy • Rheumatoid arthritis -- Hypercortisolism -- Oculomotor paresis • Spondyloarthropathy -- Hypoadrenalism • Motor neuropathy -- Isolated adrenocorticotropic hormone • Tenosynovitis deficiency -- Acute generalized motor neuropathy -- Multifocal motor block neuropathy Systemic • Autoimmune diabetes mellitus • Myasthenia gravis • Antiphospholipid syndrome • Hyperparathyroidism • Neuromyelitis optica spectrum disorders • Lupus -- Lupus nephropathy • Hypogonadism -- Optic neuritis a -- Subacute cutaneous lupus erythematosus • Hypophysitis -- Transverse myelitis -- Systemic lupus erythematosus -- Autoimmune hypophysitis • Polyneuropathiesa • Sarcoidosis -- Hypopituitarism -- Axonal sensory motor polyneuropathy -- Pan-hypopituitarism​ -- Multiplex mononeuritis -- Cutaneous sarcoidosis • Thyroiditisa -- Peripheral sensory neuropathy -- Pulmonary sarcoidosis -- Renal sarcoidosis -- Autoimmune thyroiditis • Polyradiculopathies • Sicca syndromea/Sjögren syndrome -- Hyperthyroidism -- Chronic inflammatory demyelinating -- Hypothyroidism polyneuropathy • Systemic sclerosis -- Graves disease -- Guillain–Barré syndrome • Vasculitisa -- Thyrotoxicosis -- Cerebral vasculitis Ocular -- Cryoglobulinaemia Gastrointestinal • Conjunctivitis • Enterocolitisa -- Cutaneous vasculitis • Episcleritis/scleritis -- Ileitis -- Eosinophilic granulomatosis with -- Ileocolitis • Orbital inflammation polyangiitis -- Ischaemic colitis • Uveitisa -- Giant cell arteritis -- Microscopic colitis -- Anterior uveitis -- Pulmonary vasculitis -- Ulcerative colitis -- Chorioretinopathy -- Henoch–Schönlein purpura • Hepatitisa -- Iridocyclitis/iritis aMore than 100 cases reported4.

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TCR CTLA-4 PD-1 ↓ Treg cell Anti-CTLA-4 Anti-PD-1 function and survival antibody T cell antibody

↑ T cell B cell activation

↑ Pro-inflammatory cytokines Direct ICI binding Autoantibody to cell surface production (CTLA-4-mediated)

Autoantibody-mediated ↑ T cell damage IL-17, CXCL10, TNF proliferation

T cell infiltration Tumour cell Autoantigen

Organ-specific cells Cross-reactivity

Fig. 2 | Mechanism of immune-related adverse events. The mechanisms of immune-related​ adverse events owing to immune checkpoint inhibitors (ICIs) depend on the type of ICI therapy used (anti-PD-1​ or anti-​PD-L1​ inhibitors versus anti-​ CTLA-4 inhibitors). CTLA-4 inhibitors can induce several cellular alterations, such as T cell activation and proliferation, + + impaired CD4 CD25 regulatory T cell (Treg cell) survival and increased counts of type 17 T helper cells, in addition to the induction of cross-reactivity​ between anti-tumour​ T cells and antigens on healthy cells and autoantibody production.

PD-1 and PD-L1​ inhibitors lead to a reduction in Treg cell survival and Treg cell inhibitory function and an increase in cytokine production. TCR , T cell receptor; TNF tumour necrosis factor.

who received combination immunotherapy (CTLA-4 administered with repeated injections of anti-​CTLA-4 and PD-1 inhibitors) with fatal myocarditis had robust antibodies develop anti-​pituitary antibodies, and hypo- T cell infiltration and clonal expansion with shared T cell physitis (inflammation of the pituitary gland) is an irAE receptors in both the myocardium and the tumour60. commonly observed with ipilimumab but not with PD-1 In one of the patients, a tenfold increase in expression and PD-​L1 inhibitors62. Further evidence supporting a of PD-​L1 was demonstrated in affected cardiac tissue potential role for B cells in immunotoxicity comes from compared with non-diseased​ muscle tissue60. recent data showing that patients treated with ICIs had B cell changes after a single dose, including reduced B cell-mediated​ autoantibody production numbers of circulating B cells and increased numbers Owing to increased T cell activation with ICIs, aug- of CD21low B cells and plasmablasts. These early changes mented T cell–B cell interactions can result in autoan- were strong predictors of subsequent irAEs63. tibody production. Indeed, interactions between The detection of autoantibodies during an adverse follicular T cells and B cells in germinal centres are vital event would support an immune-​mediated aetiology for humoral immunity and abnormal interactions have and could assist in guiding specific therapeutic interven- been associated with autoimmunity61. The production tion. To this end, several autoantibodies have been iden- of autoantibodies in mouse models of anti-​CTLA- tified in some patients with specific irAEs, although their 4-​induced irAEs is common62. Indeed, wild-​type mice presence is not universal across patients. For example,

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autoantibodies to thyrotropin, follicle-​stimulating hor- presentation of evolving cardiac irAEs can include mone (FSH) and corticotropin-​secreting cells have been dyspnoea (difficulty breathing), palpitations or symp- identified in patients with melanoma who received ipil- toms of congestive heart failure (such as fluid retention imumab and developed hypophysitis62. Other examples and oedema) depending on the type of cardiac dysfunc- of patients with irAEs and circulating autoantibodies tion, although preserved ventricular function assessed to specific tissues after CTLA-4 or PD-1/PD-​L1 inhi- by echocardiography does not rule out the possibility bition64 include anti-​thyroid antibodies in patients of cardiac arrhythmia77. Investigation of suspected car- developing thyroiditis, anti-​BP180 antibodies in pem- diac toxicity should include electrocardiography and phigoid, and rheumatoid factor and anti-​cyclic citrul- assessment of cardiac serum biomarkers including linated peptide in patients developing arthritis62,65–69. In creatinine kinase and troponin levels. Useful imaging addition, positive autoantibodies to diabetic autoan- assessments include echocardiography to assess left tigens including GAD65, IA-2, ICA-512, ZnT8 and ventricular ejection fraction and cardiac MRI with gad- insulin have been found in some individuals with PD-1 olinium enhancement to assess inflammation secondary inhibitor-associated​ type 1 diabetes mellitus. to myocarditis5. Cardiac biopsy is the gold standard for Despite the discovery of autoantibodies in patients diagnosing myocarditis, and characteristic pathological who have developed autoimmune diseases after receiv- findings consistent with immune cell infiltration of the ing ICIs, their frequency is significantly lower than that myocardium support this diagnosis. The involvement reported in patients with the same autoimmune disease of a cardiologist and close monitoring are necessary if who did not receive ICIs. This finding has been reported myocarditis is suspected. for type 1 diabetes mellitus26, Sjögren syndrome70,71, rheumatoid arthritis72 and myasthenia gravis73,74. The Dermatological. A wide range of dermatological man- predominant lack of serum autoantibodies may suggest ifestations of varying severity can occur in association a unique mechanism23, although whether this finding with ICIs including vitiligo, lichenoid dermatitis, psori- reflects an underlying mechanism or the inability to asis, bullous pemphigoid, granulomatous diseases, drug detect as yet unidentified autoantibodies or a very low rash with eosinophilia and systemic symptoms (DRESS), level of the specific autoantibody involved is not well Stevens–Johnson syndrome and Sweet syndrome80–83. In known8,23. most cases, dermatological toxicities occur early, and have been observed 2–3 weeks after ipilimumab treatment Direct effect of monoclonal antibody initiation and ~5 weeks after initiation of PD-1 inhibi­ As ICIs are monoclonal antibodies to molecules that tors84,85. Although common with both CTLA-4 inhi­ are expressed by both immune cells and other tis- bitors and PD-1 inhibitors, pruritis, rash and vitiligo sues, it is likely that some irAEs could be caused by are usually low grade (mild and localized or widespread complement-​mediated direct injury from these ther- and intermittent)86 (Fig. 3). Vitiligo-​like depigmentation apies. For instance, CTLA-4 is strongly expressed in is a characteristic cutaneous alteration predominantly the anterior pituitary62, and hypophysitis is primarily described in patients with melanoma who receive ICIs; seen with ipilimumab, but not with PD-1 or PD-​L1 it has been reported in some untreated individuals and inhibitors. In addition, myocardial PD-​L1 is mainly isolated cases in patients with non-​cutaneous cancer87. localized on endothelium and is critical for control Severe dermatological irAEs (that is, grade ≥3 according of immune-​mediated cardiac injury75, and a tenfold to CTCAE) occur in only 2–10% of patients receiving increased expression of PD-​L1 was demonstrated in ICIs83,88. Expert input from dermatologists should be the affected cardiac tissue in an individual with fatal sought for progressive or high-​grade skin conditions, myocarditis who received ICI combination therapy such Stevens–Johnson syndrome, toxic epidermal compared with non-diseased​ muscle tissue60. necrolysis and DRESS syndrome89. Diagnostic work-​ up typically includes a physical examination to assess Diagnosis, screening and prevention the dermatological manifestations, and skin biop- Organ-​specific irAEs sies to histologically assess aetiology according to the The incidence, typical presentation and recommended dermatologist’s clinical diagnosis90. clinical work-​up for the most frequent irAEs are summarized below (a more detailed list is included in Endocrine. The more commonly occurring endocrinop- Box 1). athies include hypophysitis, thyroid dysfunction and, less frequently, type 1 diabetes mellitus91. Endocrinopathies Cardiac. Cardiac toxicity owing to ICIs is rare (occur- are observed in up to 10% of patients who are treated ring in <1% of patients)76 but can be fulminant and with CTLA-4 inhibitors92,93 and in 4–14% of those potentially fatal. Several cardiac pathologies have been treated with anti-PD-1​ inhibitors94. reported to be associated with ICIs, of which myocarditis Hypophysitis has been reported in 3.3% of patients is one of the most common. Risk of myocarditis is higher who receive ICIs in a meta-analysis​ of 61 clinical trials, with combination therapy than monotherapy60,77. The with a higher rate in those who received CTLA-4 inhib- onset for myocarditis is relatively early, with most cases itors (4.5%) and combination therapy (7.7%), whereas developing within ~4 weeks of a single dose of ICI77. the rate in patients who received PD-1 or PD-​L1 inhib- Other cardiac irAEs include myocardial fibrosis, peri- itors was very low (<1% of individuals)95,96. Symptoms carditis, cardiomyopathy with Takotsubo-like​ syndrome, of pituitary dysfunction can be non-​specific, including acute heart failure and cardiac arrythymia78,79. Clinical fatigue, headache or weakness with additional symptoms

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a b c

d e f g

Fig. 3 | Radiological and/or photographical appearance of immune-related adverse events. a | CT image of immune checkpoint inhibitor (ICI)-​associated colitis before the onset of immune-related​ colitis. b | CT image of ICI-associated​ colitis after colitis onset. c | Vitiligo. d | High-resolution​ pulmonary CT image showing interstitial lung disease of ICI-​associated pneumonitis. e | MRI scan with T2 flair of ICI-associated​ encephalitis; an abnormal signal can be observed bilaterally in the insula and medial temporal lobes (white arrows). The patient presented with new-onset​ confusion and weakness whilst using anti-PD-1​ therapy. f | Pulmonary CT image showing multiple hilar adenopathy (black arrows) in a patient with sarcoidosis after ipilimumab treatment. Biopsy of an adenopathy demonstrated non-caseating​ granulomas. g | Cutaneous purpura in a patient treated with nivolumab.

of headache or visual changes in those with hypophysitis whereas thyroiditis or hypothyroidism have been causing pituitary enlargement97. Polyuria and polydip- reported in 6% of patients with melanoma treated with sia, representing signs of diabetes insipidus and poste- ipilimumab and in 10–22% of patients treated with ipil- rior pituitary hormone deficiency, are reported less than imumab plus nivolumab92,96,103. ICI-​associated thyroid anterior pituitary hormone deficiencies5,98. Hypophysitis dysfunction is typically mild (CTCAE grades 1–2) and can lead to secondary adrenocorticotropic hormone mainly consists of hypothyroidism (which manifests (ACTH) deficiency with secondary adrenal insuffi- with symptoms such as fatigue, increased sensitivity ciency, hypogonadotropic hypogonadism and secondary to cold, constipation or weight gain) and, less rarely, hypothyroidism owing to thyroid-​stimulating hormone hyperthyroidism (symptoms of which include weight (TSH) deficiency. Symptoms indicative of hypophysitis loss, increased appetite, palpitations, irritability, tach- should prompt an evaluation of cortisol, FSH, luteinizing ycardia or arrhythmia). Hyperthyroidism can resolve

hormone, TSH and free tetraiodothyronine (T4) levels, to normal thyroid function over time, although it can in addition to testosterone levels in men and oestrogen develop to hypothyroidism91,104. Investigation of thyroid levels in premenopausal women. MRI of the pituitary dysfunction should distinguish between primary hypo-

gland should be carried out in patients presenting with thyroidism (in which the TSH level is high with low T4 neurological deficits to rule out tumoural involvement5. levels) and secondary hypothyroidism (in which TSH

Although autoantibodies to thyrotropin, FSH and and T4 levels are low and can be representative of pitui- corticotropin-secreting​ cells and expression of CTLA-4 tary dysfunction or hypophysitis)99. Guidelines from the on pituitary endocrine cells have been described in American Society of Clinical Oncology (ASCO) recom- individuals with ICI-​associated hypophysitis, testing for mend monitoring thyroid function before ICI initiation these markers is not part of routine work-up​ 62. and every 4–6 weeks during therapy, repeating testing Thyroid dysfunction is one of the most common annually or as indicated by symptoms90. ICI-​related endocrinopathies and occurs slightly more Primary adrenal insufficiency is a less frequent irAE frequently with PD-1 inhibitors than with CTLA-4 inhib- than secondary adrenal insufficiency related to hypo- itors99,100. Primary hypothyroidism of any grade occurs physitis, with a reported frequency between 0.6% and in 8–14% of patients treated with pembrolizumab96,101,102, 2.6%94,95. In severe cases, primary and secondary adrenal

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insufficiency can lead to adrenal crisis (a life-​threatening ICI-​related hepatitis has a prevalence of 1–6% in adrenal insufficiency caused by a lack of ACTH produc- anti-​PD-1 or anti-​PD-​L1 trials, 1–25% in CTLA-4 tion in the pituitary gland in secondary adrenal insuf- inhibitor trials and 17–22% in combination anti-PD-1​ ficiency, or by lack of cortisol production in primary and CTLA-4 inhibitor trials5,13,105,106,112,115–117. The most adrenal insufficiency), symptoms of which include common presentation of hepatitis is an asymptomatic hypotension, electrolyte imbalances (particularly low rise in transaminase levels, which is observed more fre- serum sodium levels or hyponatraemia) and dehydra- quently than increased bilirubin levels (which tends to tion, and which requires immediate treatment. Low only occur in very severe or chronic cases). Hepatitis cortisol levels can indicate primary or secondary adre- screening by monitoring transaminase and bilirubin nal insufficiency, which can be further differentiated levels before initiating ICI and before every dose are with dynamic ACTH deficiency testing under specialist necessary. Individuals who develop liver enzyme abnor- guidance. A lack of ACTH stimulation during dynamic malities should undergo additional testing to rule out ACTH testing indicates secondary adrenal insuffi- viral aetiology or disease-​related hepatic dysfunction. ciency, although both primary and secondary deficiency In addition, a liver biopsy may be considered for those probably require life-long​ steroid replacement94. with higher-​grade hepatitis (defined as transaminase The ICI treatment emergent diagnosis of type 1 levels above five times the upper limit of normal) to diabetes mellitus has been reported in ≤1% of patients help expedite the identification of aetiology. For patients treated with atezolizumab or pembrolizumab in phase III treated with ipilimumab, liver biopsies demonstrated trials101,105,106. Type 1 diabetes mellitus associated with that changes overlapped with acute hepatitis, similar CTLA-4 inhibitors has not yet been reported with ipil- to findings in drug-​induced liver injury, acute viral imumab monotherapy91. Although rare, presentations hepatitis or autoimmune hepatitis118. with this irAE can be emergent, with 59% of indivi­ duals with ICI-​associated type 1 diabetes mellitus Haematological. Haematological irAEs are rare presen­ting with ketoacidosis and 42% presenting with (accounting for 3–4% of the total irAEs) but can be pancreatitis in a retrospective case series of patients potentially fatal119. The most common clinical pres- receiving PD-1 or PD-​L1 inhibitors26. Fasting glucose entations are neutropenia, autoimmune haemolytic is the preferred diagnostic test for suspected new-​onset anaemia, immune thrombocytopenia and aplastic anae- hyperglycaemia, and testing for autoantibodies (to mia119. Most haematological irAEs are asymptomatic GAD65, IA-2, ICA-512, ZnT8 and insulin) may be con- and diagnosis is based on a full blood count. However, sidered as part of a more specific work-​up, although severe cytopenias can present with fatigue and jaundice patients are not always positive for these antibodies91. (haemolytic anaemia), purpura, bruising and/or bleed- ing from mucosal surfaces (thrombocytopenia), or fever Gastrointestinal. Diarrhoea is one of the most com- and recurrent infections (neutropenia). mon irAEs, and has an incidence of ~35% for CTLA-4 inhibitors, ~20% for PD-1 inhibitors and >40% for Neurological. Neurological irAEs are rare but can cause combinatorial therapy107. By contrast, colitis (evidence substantial morbidity if not recognized and treated of inflammation of the colon) is reported in 12%, 1% early120. When all neurological irAEs are pooled, an and 14%, respectively103. Typical diagnostic work-​up incidence of 3.8% for CTLA-4 inhibitors, 6% for PD-1 for colitis can include assessments to exclude infec- inhibitors and 12% for combination therapy has been tious causes and CT to evaluate the extent and sever- reported in one review of 59 clinical trials121. Several ity of colitis and rule out bowel perforation (Fig. 3). neurological irAEs have been reported, including Endoscopy is not routine for mild cases of colitis as peripheral neuropathies (reported in 1.3% of individu- correlation between the grade of diarrhoea and endo- als with ICIs), myasthenia gravis (1.2%), myelitis (0.8%), scopic features of colitis severity is poor108, but it can meningitis (0.4%), encephalitis (0.3%) or Guillain–Barré be helpful when the diagnosis is elusive, in those with syndrome (<0.1%)121,122. severe, refractory or recurrent colitis, to guide biopsy Several peripheral neuropathies have been asso- for the exclusion of cytomegalovirus-​associated colitis ciated with ICIs, including non-​length-​dependent or to examine high-​risk features that can guide esca- poly­radiculoneuropathies, small-​fibre/autonomic lation of therapy (ulceration or extensive colitis)107,109. neuropathy, mononeuritis multiplex, sensory neuronop- On colonoscopy, CTLA-4 inhibitor-​related colitis can athy and length-​dependent sensorimotor axonal poly- show mucosal erythema and ulcerations similar to those neuropathy123. Individuals with suspected neuropathies in Crohn’s disease, although findings can be variable110. should undergo evaluation for alternative causes as they Colonic biopsies from individuals with ICI-associated​ could be caused by other medications, infectious disease colitis have shown both neutrophilic and lymphocytic and metabolic, endocrine or vascular disorders. Nerve inflammation, with a substantial histological overlap conduction studies can be useful in this regard5. with other aetiologies of colitis making the differential A symptom of myasthenia gravis is muscle weakness, diagnosis difficult111. Fatal intestinal perforation in indi- commonly affecting the face. One review of 23 cases73 of viduals with severe colitis has been reported in up to 1% myasthenia gravis reported an average onset of symp- of patients who received ipilimumab, which was more toms within 6 weeks of initiating therapy and two-thirds​ commonly related to higher doses of ipilimumab or of cases presenting with severe symptoms, with bulbar ipilimumab combinatorial therapy with radiotherapy symptoms and myasthenic crisis (severe muscle weak- or other treatments112–114. ness requiring respiratory ventilation) being observed

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more frequently in ICI-​associated myasthenia gravis Renal. An overall incidence of 2.2% was reported for than in idiopathic cases73. acute kidney injury (0.6% for grades 3 and 4 renal Patients presenting with headache, neck stiffness and events) in one systematic review of randomized con- photophobia (extreme sensitivity to light) whilst using trolled trials including 3,695 patients treated with ICIs133, ICIs should raise a suspicion for aseptic meningitis, although more recent studies have suggested a higher which can be clinically distinguished from encephalitis frequency134. Increased serum creatinine levels are an owing to preserved mental status with aseptic menin- almost universal feature of ICI-​induced renal toxicity gitis (if mental status changes and seizures are present, and most renal irAEs occurred 6–12 weeks following encephalitis should be suspected). Investigations should the start of ICI treatment134. An evaluation of potential include brain MRI with and without contrast in individu- alternative nephrotoxic therapies or contrast agents is als with suspected meningitis or encephalitis, in addition suggested in individuals with newly increased creatinine to lumbar puncture to identify infectious causes (par- levels. In addition, investigation of urinary protein is rec- ticularly viral aetiology) and electroencephalography to ommended, followed by an autoimmune screen, includ- assess for subclinical seizures (Fig. 3). ing anti-​nuclear antibody, anti-​neutrophil cytoplasmic antibody, rheumatoid factor, anti-double-​ stranded​ DNA Ocular. Ocular irAEs encompass inflammation of the antibodies and serum complement levels, which might eye, which can include uveitis, episcleritis, conjunctivitis offer insights into the underlying pathological process5. and orbital myopathy, with an incidence of <1%124. Onset Clinical findings and laboratory tests are suboptimal in of uveitis associated with CTLA-4 inhibitors is usually diagnosing the underlying renal lesion, making a kidney CTCAE grades 1 or 2 (ref.125). Symptoms of inflamma- biopsy necessary in the majority of cases to definitively tion in the eye can include photophobia, pain in the diagnose the type of renal damage and potentially guide orbital region, dryness and blurry vision126. A change therapy135. Pathological features have been described in vision should prompt vision testing under the guid- as ranging from acute tubulointerstitial nephritis to ance of an ophthalmologist to assess visual acuity, pupil granulomatous features and evidence of thrombotic reactivity and fundus changes to diagnose uveitis89. microangiopathy.

Pulmonary. Pneumonitis (focal or diffuse inflammation Systemic and rheumatic. Systemic and rheumatic irAEs of the lung parenchyma) is a relatively rare irAE that have mainly been reported in retrospective studies and is potentially life-​threatening117,127. Pneumonitis has an case reports, and can be clustered into articular (with incidence of ~1% and 3% in individuals who received a prevalence of 36% in the ICIR-​BIOGEAS Registry), PD-1 or PD-​L1 inhibitor monotherapy for melanoma, muscular (prevalence of 34%), granulomatous (preva- non-​small-​cell lung cancer and renal cell carcinoma128, lence of 6%), vasculitic (prevalence of 12%) and systemic with the highest incidence of all-​grade and high-​grade (prevalence of 12%) irAEs136. pneumonitis in patients with non-small-​ cell​ lung cancer The most frequent articular irAEs are inflammatory (3.1%)129. One study reported a significantly higher fre- arthralgias, arthritis (which manifest as joint inflamma- quency of all-grade​ interstitial lung disease (3.6% versus tion and pain) and polymyalgia rheumatica (which man- 1.3%) and high-​grade interstitial lung disease (1.1% ver- ifests as stiffness and pain in the shoulders and hips). The sus 0.4%) in patients treated with PD-1 inhibitors than frequency of arthralgias in randomized controlled trials those who received PD-L1​ inhibitors130. However, some of ICIs is 8% and they are classified as mild (CTCAE studies have reported a higher incidence, such as one grades 1 or 2) in >95% of cases, whereas arthritis has study of durvalumab treatment after chemotherapy and been reported in 1% of individuals4. The key features of radiotherapy in individuals with stage 3 non-small-​ ​cell articular irAEs include a median onset time of 70 days lung cancer with an incidence of 34%, supporting the after ICI commencement, a predominance of seronega- hypothesis that radiotherapy could be a risk factor for tive arthritis (80% of individuals) and, among individu- pneumonitis131. als with available information about the distribution of Patients with pneumonitis present most commonly the arthritis, ~60% were classified as polyarthritis23,137–140. with dyspnoea and cough, but can also present with Well-characterized​ inflammatory arthritis such as rheu- fever or chest pain102, or as asymptomatic radiological matoid arthritis or psoriatic arthritis have been reported findings in some individuals. The median time to onset in ~30 individuals, with isolated reported cases of other of treatment-​related pneumonitis for nivolumab was forms (spondyloarthropathy, reactive arthritis-like,​ ste- 15.1 weeks in one study132. Suspicion of pneumonitis nosing tenosynovitis, Jaccoud arthropathy, RS3PE syn- should be investigated by checking oxygen saturation drome, enthesitis or osteonecrosis)4. Patients receiving on room air and whilst ambulatory, ruling out an infec- ICIs should be asked about joint symptoms and referred tious aetiology, and CT to exclude alternative causes as soon as possible to a rheumatologist if arthritis is sus- and to evaluate the extent of inflammation. CT find- pected for diagnostic work-​up, which includes ultra- ings can be variable and include the following patterns: sonography, CT or MRI studies and analysis of serum cryptogenic-​organizing, pneumonia-​like, ground-​glass inflammatory parameters and autoantibodies. opacities, interstitial with interlobular septal thickening, Muscular features can include myalgias and myositis, hypersensitivity with a bronchiolitis-​like appearance typical symptoms of which include varying degrees of and tree-​in-​bud102 (Fig. 3). Bronchoscopy can also be muscle weakness and pain. The frequency of myalgias helpful to establish diagnosis, particularly if alternative is 4% in randomized controlled trials, and they are often aetiologies are under consideration5. classified as mild (CTCAE grades 1 and 2), whereas

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myositis has been reported in 0.6% of individuals receiv- sialadenitis via histopathological analysis of minor sali- ing ICIs4. Myositis is predominantly reported without a vary glands. In addition, isolated cases of systemic scle- detailed clinical, immunological and histopathological rosis, lupus and antiphospholipid syndrome have been characterization, with well-characterized​ inflammatory reported in individuals receiving ICIs24,138,148,149. myopathies (dermatomyositis and polymyositis) being reported in ~20 cases, with most cases being positive Screening and prevention for myositis-​related autoantibodies. Two specific stud- Safety and efficacy in patients with pre-​existing auto­ ies141,142 have characterized ICI-associated​ inflammatory immune diseases. As ICIs can induce irAEs, and given myopathies, and have reported a mean time of onset that patients with pre-​existing autoimmune diseases of 25 days after ICI initiation and an association with were excluded from clinical trials of ICIs, the safety other muscular irAEs (16–40% of people with inflam- and efficacy of these drugs in this population is a key matory myopathies also had myocarditis or myasthenia issue to be addressed before extending treatment gravis) and hepatitis (found in 8–10% of individuals recommendations to include these patients. with inflammatory myopathies). In addition, ICI-associated​ Several studies have suggested an enhanced risk of inflammatory myopathies are associated with high irAEs in patients with pre-​existing autoimmune dis- mortality (21%), which was higher in patients who also eases. A systematic review that included 123 patients developed myocarditis (52%)141. Patients with a sus- with pre-existing​ autoimmune disease who were treated pected ICI-​associated inflammatory myopathy should for cancer by ICIs150 demonstrated autoimmune dis- be investigated for raised serum muscular enzymes and ease exacerbation in 50% of individuals, de novo irAEs myositis-​related autoantibodies (Jo-1, PL-7/12, EJ, OJ, in 34% and no autoimmune symptoms in only 16%. Mi-2, SRP, TIF, MDA5, PM-Scl,​ Ku, RNP and Ro), and Interestingly, no difference was observed in patients muscular involvement should be objectively assessed with active versus those with inactive pre-​existing using electrodiagnostic and imaging studies and, autoimmune disease, and patients receiving treatment whenever possible, with histopathology. for their autoimmune disease at initiation of cancer Granulomatous disorders, predominantly sarcoido- immunotherapy had fewer adverse events (59%) than sis (Fig. 3), are also an increasingly recognized irAE those who did not receive treatment at initiation of in patients treated with ICIs4,143. A review of 23 cases immunotherapy (83%). Further evidence supporting reported that sarcoidosis developed between 3 and an increased risk of irAEs in those with autoimmune 36 weeks after treatment initiation, with the lymph disease is based on data from the systematic REISAMIC nodes, lungs and skin being the primary affected organs, registry151; the prevalence of irAEs was higher in patients although other systemic manifestations have also been with pre-​existing autoimmune diseases (44%) than in reported144. A thoracic CT is mandatory in patients with patients without autoimmune diseases (29%), and 55% suspected sarcoidosis. Histopathological confirmation of irAEs in patients with previous autoimmune dis- of non-​caseating granulomas in the absence of cancer ease were related to the same autoimmune disease and progression and other causes (especially infectious) of 45% were new-​onset irAEs. In this study, ICIs were granulomatosis is highly recommended for diagnosis. stopped only in 5 of 20 patients with irAEs and the over- Almost 200 cases of vasculitis associated with cancer all survival of the patients with previous autoimmune immunotherapies have been reported, 64% of which are diseases was the same as in the patients without. In many related to ICIs, mainly presenting with cutaneous pur- patients, irAEs were manageable with corticosteroids pura and less frequently as neuropathy or visceral vascu- (only 16% required other immunosuppressive thera- litis4. On the basis of the size of the vessel affected, giant pies) and discontinuation of ICIs was required in 17% cell arteritis is the most frequently reported systemic of patients in the systematic literature review150 and in vasculitis (of which 28 cases have been reported145), with 11% of individuals in the Gustave Roussy experience151. isolated reported cases of Henoch–Schönlein purpura, Thus, even if the risk of irAEs is higher in patients with cryoglobulinaemic vasculitis and eosinophilic granu- pre-​existing autoimmune disorders, there is no reason lomatosis with polyangiitis4,146. Patients with suspected to exclude these patients from cancer immunotherapy152. vasculitis should be investigated for the presence of The rates of reactivation or flare of the pre-​existing anti-​neutrophil cytoplasmic antibodies and cryoglobu- autoimmune diseases after initiating ICIs150,151,153–159 are lins, and vascular involvement should be assessed using summarized in Fig. 4 and discussed in the Supplementary imaging and, whenever possible, with histopathological Information. study. Sicca syndrome (the development of oral and/or Autoimmune screening before starting therapy. One ocular dryness) has been reported in 5% of patients of the most common factors that predisposes to auto­ receiving ICI monotherapy and 10% of those receiving immune disease is the presence of autoantibodies with- combination therapy in randomized controlled trials4. out clinical signs160. Some patients with irAEs might have Twenty-​two cases of Sjögren syndrome triggered by pre-​existing subclinical autoimmune conditions that ICIs have been reported, predominantly related to the manifest clinically as a full autoimmune disease after ICI use of PD-1 inhibitors71,147. Patients presenting with therapy. There is no argument for recommending uni- sicca symptoms after being treated with ICIs should be versal screening for autoantibodies before initiating ICI, investigated for the presence of abnormal function of as even if an individual has a positive screen, it would lachrymal and parotid glands, positive autoantibodies not be a contraindication for treating them with ICIs for (mainly for anti-​Ro antibodies) and focal lymphocytic cancer therapy. However, in patients with a personal or

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Polymyalgia rheumatica (17) Myasthenia and/or myositis (14) Rheumatoid arthritis (86) Psoriasis or psoriatic arthritis (118) Other arthritis (*) (9) Inflammatory bowel disease (52) Sjögren syndrome (11) Autoimmune cytopenias (*) (11) Systemic sclerosis (16) Sarcoidosis (20) Spondyloarthropathies (8) Other cutaneous (*) (9) Vitiligo (22) Demyelinating CNS (*) (18) ANCA vasculitis (7) Thyroiditis (91)

Lupus (17) >50% PRP/cranial palsies (*) (9) 25–50% Large/medium vasculitis (*) (5) <25% Other digestive (*) (6)

0 10 20 30 40 50 60 70 80 Frequency of relapse (%)

Fig. 4 | Rate of reactivation/flare of pre-existing autoimmune diseases after immune checkpoint inhibitor therapy. Rates of reactivation/flare were defined as ‘number of patients who relapsed/total number of patients exposed to the drug’, to be calculated for each underlying autoimmune disease. Rates in individual diseases or grouped diseases (marked as *; see the corresponding definition in the Supplementary Information) with at least five treated individuals are represented. Information about the use of immune checkpoint inhibitors in patients with cancer and pre-existing​ autoimmune diseases was extracted from nine studies150,151,153–159 after searching MEDLINE for articles published up to 1 January 2020 using the terms “pre-existing​ (preexisting)” and “autoimmune” in combination with “checkpoint”, “CTLA-4”, “PD-1” and “PD-L1”,​ with no search restrictions. Study designs were considered in the following order (listed from the highest to the lowest evidence quality): systematic reviews, controlled trials, prospective cohort studies, case–control studies, retrospective studies and case series. The following relevant information was defined as the selection criteria: a well-defined​ “population at risk” (patients diagnosed with an autoimmune disease before the initiation of the immune checkpoint inhibitor therapy), available information to calculate the rate of relapse (patients who relapsed/total number of patients exposed to the drug, to be calculated for every different type of underlying autoimmune disease), and whether the relapse was linked to the underlying autoimmune disease. Duplicate publications, case reports, experimental studies and articles including incomplete/irrelevant information were excluded. We also manually searched the reference list of relevant articles retrieved and the EMBASE database (a flow diagram of search results is included in the Supplementary Information). The total reported cases are in parentheses. ANCA, anti-neutrophil​ cytoplasmic antibody; CNS, central nervous system; PRP, platelet-rich​ plasma.

familial history of autoimmune disease, or in those who antibodies162, dermatological irAEs in those with presented signs or symptoms suggestive of an underlying anti-​BP180 antibodies163, colitis in patients with anti-​ autoimmune disease, screening for autoantibodies may nuclear antibodies164, hypophysitis in those with be considered before starting an ICI as these patients anti-​GNAL antibodies or anti-​ITM2B antibodies and have an enhanced risk of developing a full auto­immune pneumonitis in those with anti-CD74​ antibodies165. B cell disease after treatment and, therefore, should be followed changes detected after a median of 3 weeks since starting up more closely. ICI therapy (reduced number of total B cells, increased percentage of CD21low B cells and plasmablasts and Potential markers predicting occurrence of irAEs. Some greater clonality in CD21low B cells) have also been biomarkers that are present before starting ICI therapy are suggested to help identify patients at increased risk of associated with a high risk of occurrence of irAEs. Several irAEs63. Serum cytokine levels might also provide pre- studies have linked the presence of pre-​therapeutic dictive value and mechanistic insight for patient suscep- serum autoantibodies with an increased risk of some tibility to ICI-​induced irAEs; for example, pre-​existing irAEs8, such as myositis in patients with anti-​mAChR circulating IL-17 levels may help to predict which patients antibodies161, thyroiditis in patients with anti-​thyroid with ipilimumab-treated​ melanoma could develop severe

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diarrhoea and colitis, since patients who developed provide symptom relief in patients presenting with acute CTCAE grade 3 colitis had higher mean IL-17 serum inflammation of the pituitary or thyroid gland168. The levels than those who presented with grades 0–2 coli- prophylactic use of glucocorticoids is not recommended tis166. All these data have to be confirmed in larger studies for the prevention of irAEs; one study showed that the before recommending their use in clinical practice. development of diarrhoea or colitis was not prevented in patients receiving ipilimumab monotherapy169. Management Therapeutic management Hormonal replacement. Patients with symptomatic Treatment of irAEs depends on the organ system affected thyroid dysfunction, hypopituitarism, hypoadrenalism and the grade of toxicity according to the CTCAE classi- or type 1 diabetes mellitus are typically given replace- fication, although it should be emphasized that common ment hormones or insulin. Patients rarely recover fully CTCAE grading might not be useful for grading the from these irAEs and so often require permanent treat- severity of some complex irAEs (such as systemic and ment94,170, especially for the corticotrope axis dysfunc- rheumatic irAEs). Therapeutic algorithms have been tion. In addition, withholding ICI is not required for developed by several organizations to help simplify and endocrinopathies unless the patient is symptomatic or effectively diagnose and manage these adverse effects unstable. ICI treatment can resume once replacement (such as ASCO, the National Comprehensive Cancer therapy or treatment is started for the endocrine irAE89. Network, the European Society of Medical Oncology, the Society for Immunotherapy of Cancer and the European Immunosuppressive agents. If irAEs do not markedly League against Rheumatism)88–90,152,167. To summarize, improve within 48–72 h of steroid treatment or cannot patients with CTCAE grade 1 irAEs typically do not be tapered without a flare of the symptoms then syn- require interventional treatment and, in most cases, ICIs thetic immunosuppressive agents should be added as can be continued or temporarily halted with close moni- glucocorticoid-​sparing agents, with no evidence sup- toring. Patients with grade 2 adverse effects should stop porting the choice of one drug over another. For exam- ICIs until adverse effects abate, although glucocorticoids ple, mycophenolate-​containing immunosuppressants can be considered in some individuals depending on the can be used for the management of steroid-​refractory severity of the organ-​specific damage or if irAEs persist irAEs, particularly for immune-related​ hepatitis, nephri- after ICI therapy is stopped, whereas patients presenting tis, pancreatitis and uveitis, whilst patients with steroid-​ with grade 3 or grade 4 irAEs should initially receive refractory pneumonitis can be treated with either steroids. In general, grade 1 irAEs can be treated and mycophenolate or cyclophosphamide89, and those with monitored by the patient’s oncologist (particularly for arthritis can receive hydroxychloroquine or metho- non-​bullous dermatitis, colitis, hepatitis, ocular, renal, trexate171. Other immunosuppressive therapies have musculoskeletal and haematological irAEs), whereas been less frequently used for corticosteroid-​refractory patients with grade 2 or higher irAEs or those with irAEs including tacrolimus, cyclosporine and sulfasala- symptomatic endocrine irAEs such as diabetes mellitus zine89. Use of these drugs should be considered only or thyroid disease should be referred to a specialist. For for refractory irAEs in consultation with appropriate some organ-​specific irAEs (pancreatitis, hypophysitis, disease-specific​ specialists. pneumonitis, neurological, rheumatic and systemic autoimmune diseases), referral to a specialist should be Intravenous immunoglobulin and plasma exchange. strongly considered regardless of CTCAE severity. Intravenous immunoglobulin is used as a second-​line Here, we follow a pharmacologically guided sched- therapy for neurological and haematological irAEs172. ule about the overall therapeutic approach for irAEs; for IrAEs that are caused directly by autoantibodies, such as more detailed organ-by-​ ​organ management guidelines, some haematological or neuromuscular irAEs, can also the reader is directed to the other guidelines88–90,152,167. be treated by plasma exchange173 (Fig. 5), which can remove the pathogenetic autoantibody from the cir- Glucocorticoids. Glucocorticoids are the mainstay of culation and is particularly effective in severe cases of treatment for irAEs except for endocrine irAEs (Fig. 5). myasthenia gravis or Guillain–Barré syndrome. Prednisone is usually the preferred corticosteroid and the dose varies depending on the grade and clinical Monoclonal antibodies. Non-​controlled descriptive severity88–90,167 and, for most irAEs, is tapered slowly studies have suggested the use of infliximab (a TNF over 4–6 weeks if clinical improvement is confirmed inhibitor174) for severe, refractory, immune-​related within days of steroid initiation. In those with grade 3 or colitis or inflammatory arthritis. In most cases, only a grade 4 irAEs, methylprednisolone pulses can be started, single dose of infliximab is required to improve these and if clinical improvement is confirmed after 48–72 h, irAEs; however, a second dose 2 weeks later is required this is tapered slowly over 4–6 weeks. As a general rule, in some patients175. One study has demonstrated that the glucocorticoids should be used at the minimum dose front-​line addition of infliximab to glucocorticoids for and length of time necessary to control active systemic grades 3 and 4 colitis was associated with a significantly disease and, in case of anticipating a prolonged use, shorter time to symptom resolution than in patients there is a need to introduce steroid-​sparing strategies who received glucocorticoids alone176. In a mouse or early initiation of anti-​TNF and other monoclonal model of colon cancer, anti-​TNF monoclonal antibod- antibodies. Although endocrine irAEs are common, ies prevented the occurrence of colitis when concomi- they rarely require treatment with steroids; steroids can tantly administered with combined CTLA-4 and PD-1

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IL-6

Integrin B cell TNF irAE c TNFa IL-6 Various

TNF Various

SAD First line

Arthritis b

Colitis ILD Other Endocrine options

Myocarditis TNF Avoid and/or

B cell AIHA/ITP Hepatitis caution

Uveitis

Neuropathy Pancreatitis TNF

Nephritis Myelitis

Encephalitis irAE Myasthenia Glucocorticoids

Integrin Synthetic immunodepressants Intravenous immunoglobulins B cell Plasma exchanges

Integrin Monoclonal antibody target Hormonal supplementation

Fig. 5 | Suggested therapeutic algorithm for the organ-by-organ management of irAEs. When a systemic therapy is considered in patients presenting with immune-related​ adverse events (irAEs) owing to immune checkpoint inhibitors, the first-line​ treatment is glucocorticoids with an exception for adverse events that affect the endocrine system. Other therapies to be considered in severe/refractory cases depend on the affected organ system but can include synthetic immunosuppressants, intravenous immunoglobulin, plasma exchange and monoclonal antibodies. These therapeutic suggestions are based on recommendations included in official guidelines, data from some retrospective studies, isolated published cases and personal experience of the authors. aAvoid etanercept owing to the risk of autoimmune inflammatory colitis. bConsider abatacept or alemtuzumab. cConsider infliximab or tocilizumab. AIHA/ITP, autoimmune haemolytic anaemia/immune thrombocytopenic purpura; ILD, interstitial lung disease; SAD, systemic autoimmune diseases; TNF, tumour necrosis factor.

inhibitors and increased survival, providing clinically response syndrome or cerebritis) reported a clinical feasible strategies to dissociate efficacy and toxicity in improvement in 80% of those who received tocilizumab, human trials177. Before administering TNF inhibitors, which, in most cases, required only 1–2 doses to cause tests to identify infectious disease, such as a tuberculo- clinical improvement181. Another study has reported sis spot test, should be performed as TNF inhibitors can the effective use of tocilizumab in three cases of severe increase the risk of reactivation of certain infections89,174. polyarthritis56. Vedolizumab (a monoclonal antibody to the integrin Other monoclonal antibodies have also shown some α4β7 that inhibits the migration of T cells into inflamed promise for the treatment of some steroid-​refractory gastrointestinal mucosa) can be used instead of inflix- irAEs. Rituximab has shown efficacy for the treatment imab for immune-​related colitis178. The theoretical of glucocorticoid-​refractory cases of severe enceph- advantage of using vedolizumab is that the immunosup- alitis182, autoimmune cytopenias183 or severe bullous pression would be limited to the gastrointestinal tract skin disease184. In addition, two cases of successful and, therefore, spares the systemic immune suppression. response to abatacept185 or alemtuzumab186 have been In a retrospective study of patients refractory to ster- reported in patients with steroid-refractory​ autoimmune oids (n = 19) and infliximab (n = 9) who received vedol- myocarditis. izumab, 86% achieved a sustained clinical remission and Despite the benefits of monoclonal antibodies for the 54% achieved an endoscopic remission179. treatment of steroid-refractory​ irAEs, they are associated Tocilizumab (an anti-​IL-6 antibody) has been sug- with specific adverse effects that may preclude their use gested for the management of some steroid-​refractory for some irAEs (Fig. 5). For example, anti-TNF​ antibodies irAEs180. One study in patients with nivolumab-​ should be used with caution for treating pneumonitis associated grades 3–4 irAEs (n = 34; predominantly because there is a risk of exacerbating interstitial lung pneumonitis, serum sickness and systemic inflammatory disease187, whereas using etanercept and tocilizumab to

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treat colitis is cautioned against owing to their associa- were the use of corticosteroids or infliximab193. Owing tion with increased risk of inflammatory bowel disease188 to the overlap with intestinal, pulmonary and hepatic and increased risk of perforation in patients with Crohn’s irAEs, some opportunistic infections should always be disease189,190, respectively. Moreover, some cases of pro- ruled out in patients in whom irAEs did not improve or gressive multi-​focal leukoencephalopathy during ther- worsened despite treatment with immunosuppressive apy with natalizumab (an anti-α4-​ ​integrin monoclonal agents. Infections to be ruled out include cytomegalo- antibody) — although not with vedolizumab191 — have virus194 and Clostridioides difficile195 in refractory colitis, been reported and the use of anti-​integrin monoclonal Pneumocystis pneumonia, pulmonary aspergillosis196 antibodies for neurological irAEs should be proposed and tuberculosis197 in pneumonitis, and viral infections only with caution. or reactivations (hepatitis B virus and cytomegalovirus) in hepatitis198–200. Thus, a history of previous infections Follow-​up and monitoring and risk factors for viral infections such as HIV or viral The therapies used for the management of irAEs can hepatitis should be evaluated before individuals with be associated with adverse effects, some of which can be cancer are given ICIs197,201, although a chronic viral severe. Whether treatment for irAEs affects the treat- hepatitis infection with negative viraemia is not a con- ment of the cancer (Box 3) and when to reintroduce ICIs traindication for an ICI prescription as shown in liver to the patient are important questions. carcinoma studies with PD-1 inhibitors202.

Adverse effects and infections. Most irAEs resolve a Re-​challenge. In the ASCO and European Society of median of 4–8 weeks after the ICI is stopped, or with Medical Oncology guidelines, permanent discontinua- the addition of glucocorticoids in severe cases115,192. tion of the ICI is recommended for all grade 4 irAEs, and Close monitoring is mandatory to detect a relapse of the ASCO guidelines recommend permanently stopping the irAE or a complication resulting from immunosup- ICIs for those with grade 3 myocarditis, pneumonitis, pressive therapies. Some adverse effects can be easily nephritis, hepatitis and severe neurological toxicities. identified, such as worsening of pre-​existing diabetes In the remaining cases, the oncologist has to determine mellitus, hypertension and mood disorders, whereas whether a patient will benefit from the reintroduction of others, such as infections, are more challenging to detect. ICI therapy (re-challenge)​ once the irAE has resolved. Although ICIs do not seem to directly increase the risk No randomized phase III trials evaluating ICI of infection191, the use of immunosuppressive thera- re-​challenge after the resolution of grade ≥2 irAEs pies and biological agents to treat irAEs may increase have been published, and the main evidence availa- the risk193. A retrospective study in 740 patients with ble comes from studies with more than ten patients melanoma who received CTLA-4 and/or PD-1 inhib- re-​challenged203–206. These studies showed that 33–50% itors identified severe infections (defined as infection of the patients who had an irAE during treatment with requiring hospitalization or parenteral antimicrobials) in a PD-1 or PD-L1​ inhibitor had a recurrent or new-onset​ 54 (7%) patients (steroids were used in 46% and inflix- irAE after reintroducing PD-1 or PD-​L1 inhibitors, in imab in 16% of these patients). In this study, oppor- contrast to 18–21% of those who had an irAE during tunistic infections were reported but most infections combination treatment (with CTLA-4 and PD-1 inhib- were bacterial pneumonia or septicaemia, and the main itors) after reintroducing only PD-1 inhibitors. Three factors significantly associated with severe infection deaths were reported in patients re-​challenged due to Stevens–Johnson syndrome, colitis and hepatic fail- Box 3 | Treatment of irAEs without affecting cancer treatment ure, and pneumonitis. In all of these studies, patients Whether the use of steroids and/or immunosuppressants to treat immune-related​ with myocarditis or severe neurological irAEs were not adverse events (irAEs) could reduce the efficacy of cancer immunotherapy has been re-challenged;​ therefore, data from these conditions are evaluated in several studies. In this regard, results from retrospective studies on lacking. melanoma were reassuring; steroid use was not associated with a loss of efficacy of The decision to re-​challenge should be based on the CTLA-4 inhibitors and PD-1 or PD-L1​ inhibitors257,258; however, prospective studies are potential risk-​to-benefit​ ratio for each patient. When to needed to determine the effects of steroid use on the outcomes of other cancers. re-initiate​ ICIs should be decided by a multi-​disciplinary In lung cancer, the use of ≥10 mg of prednisone equivalent upfront has been associated committee involving organ specialists in each cancer with poorer outcome, but the irAEs were not the only indications for steroid use centre to provide recommendations with a personal- 259 (common indications were dyspnoea, fatigue and brain metastases) . Two different ized care or patient-​centred approach. No risk factors situations could be considered based on these results: if steroids are used before associated with irAE relapse after re-​challenge have been commencing immune checkpoint inhibitors for cancer-related​ indications, a dose of clearly identified except for a shorter time to the initial >10 mg daily may be deleterious259, whereas no deleterious effect has been demonstrated so far for the use of steroids for the treatment of irAEs. Interestingly, irAE and the increased risk of relapse after resumption progression-​free survival was longer in patients with urothelial cancers who developed of CTLA-4 inhibitors than resumption of PD-1 or PD-L1​ irAEs than in those who did not, and this benefit was not altered by steroid use260. inhibitors206. Despite these trials showing no effect on cancer outcomes with treatment for irAEs, other studies have suggested that caution is needed. For example, glucocorticoids Quality of life have been suggested to promote breast cancer metastasis261 through activation of the Health-related​ quality of life glucocorticoid receptor. In addition, another study has suggested that clinically relevant Studies have addressed the health-​related quality of life doses of infliximab only had a minor influence on the activity of tumour-​specific T cells issues faced by people with irAEs, and these have been in vitro, whereas even low doses of corticosteroids markedly impaired the anti-​tumour shown to have a greater effect in older patients207. Several activity of tumour-​specific T cells262. studies have demonstrated that ICIs are well tolerated

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compared with other anti-​cancer therapies208–210 and deaths occurred early after ICI initiation with combina- even grade 3 and grade 4 irAEs do not translate into tion therapy, with a median time from symptom onset to clinically meaningful differences in health-related​ qual- death of 14.5 days in comparison with 32 days for mono­ ity of life211. By contrast, other studies have demonstrated therapy222. Myocarditis has the highest demonstrated significantly lower health-​related quality of life scores mortality, with 48% of 351 individuals included in the than in the general population212,213, with an increased two main studies dying224,225. The death rate from myosi- psychological morbidity214 or a potential effect on cog- tis is reported to be 20% of 204 individuals138,141,226,227 in nitive function of surviving patients who received these whom the principal cause of death was associated myo- therapies215. More people with melanoma and brain carditis141,227. A similar death rate has been reported for metastases are surviving for longer because of ICIs, and ICI-​associated myasthenia gravis (26% of individuals efforts to further comprehensively address psychosocial, (n = 35)73,74), whereas the rate is lower for colitis (6%)225. neurocognitive and health-related​ quality of life issues in Other irAE-​related deaths have been reported for inter- this population are ongoing213. stitial lung disease228–230, hepatitis229, Guillain–Barré syndrome114 or autoimmune cytopenias231. Outcomes Patients who develop irAEs often show a better ther- Outlook apeutic response to cancer than those who do not International efforts are needed to develop evidence-​ develop irAEs, suggesting a close link between auto­ based multi-​disciplinary management guidelines for immunity and the anti-​tumour effect elicited by irAEs, to improve the clinical characterization and ICIs100,216. Indeed, a growing body of evidence suggests diagnosis of irAEs, and to anticipate that the rapid that patients who have irAEs have marked improve- incorporation of certain novel therapeutic approaches ments in progression-​free survival, overall survival and could increase the diversity and severity of irAEs. The overall response rate than those who did not develop an main aim of future research should be the development irAE, with more consistent data in patients treated with of more effective therapeutic management, which will PD-1 and PD-​L1 inhibitors216 than in those treated require further clinical trials, and efforts to develop with CTLA-4 inhibitors3. Of the different organ-specific​ more precise mechanistic studies to learn more about irAEs that are associated with enhanced survival, the the pathophysiology. most consistent data are from dermatological irAEs, particularly rash and vitiligo217,218. However, many ques- Implications for treatment tions remain about what irAE-​specific factors (such as The risk of irAEs with ICIs has several implications the affected organ, severity, timing of onset or thera- for cancer treatment, namely, whether the use of these peutic intervention) could have a prominent role in therapies is appropriate and efficacious in individuals contributing to the increased survival216. with chronic disorders. Data are now emerging from Despite these apparent benefits in terms of cancer early phase II trials and case reports that suggest dura- outcomes, the development of irAEs has been related ble responses and a manageable safety profile of ICIs to an irreversible organ damage, which, in some cases, in patients with controlled hepatitis B virus or hepati- can be fatal. Irreversible organ damage is most fre- tis C virus infection232. With respect to the use of ICIs quently reported for irAEs of the endocrine system, in patients with HIV, no unexpected irAEs have been which predominantly result in permanent damage or observed233. By contrast, data from case series suggest destruction of the endocrine organs and often require that there is a high risk of graft rejection with PD-1 and chronic therapy60. In addition, PD-1 inhibitors have been PD-​L1 inhibitors in patients with solid organ trans- associated with a higher incidence of grade 3 or grade 4 plantation and, although responses to ICIs have been pneumonitis (leading to irreversible fibrotic pulmonary observed, the use of these therapies in this population damage)219, and severe colitis might require colectomy should be weighed against the risk234. Tolerance of ICIs in some patients who have perforation220. Moreover, in those ≥65 years of age seems similar to that in younger isolated cases of non-​resolved xerostomia, alopecia or individuals34, although older patients should be closely vitiligo with ICIs have been reported221. monitored for cardiovascular disease235. Compliance The global irAE-​associated mortality is estimated to with vaccine recommendations is also important for be ~0.6% in patients treated with ICIs, with individual protecting patients with cancer who are immuno­ rates of 0.36% for patients who received PD-1 inhibitors, compromised236, and one study has demonstrated that 0.38% for those who received PD-​L1 inhibitors, 1.08% influenza vaccination in patients with lung cancer receiv- for those who received CTLA-4 inhibitors and 1.23% for ing PD-1 inhibitors does not induce irAEs237. With this individuals who received combination therapy222,223. complex clinical scenario, a multi-disciplinary​ approach The causes of death differed widely between regimens; is mandatory238, with a central role for an oncologist239, for example, 70% of CTLA-4-​related deaths were due rheumatologist240 and internist241, together with the to colitis, whereas deaths associated with PD-1 and support of a specialist in the affected organ(s). PD-​L1 inhibitors were often from pneumonitis (35%), hepatitis (22%) and neurotoxicity (15%)222. Among Improving clinical characterization patients who received combination therapy (with PD-1 The wide heterogeneity of both pharmacological and and CTLA-4 inhibitors) and died, 37% of deaths were clinical scenarios of irAEs, together with the increas- caused by colitis and 25% by myocarditis222. In addition, ing identification of these events, suggest that the use the time to death varied depending on the ICI used; of artificial intelligence (machine learning) and big data

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(incorporating large volumes of information into com- are being carried out worldwide, but the knowledge from puters) will have a key role in optimizing clinical char- this microbial therapy is still limited, especially with acterization242,243. A key limitation for optimal clinical respect to how the viabilities of transplanted micro­ characterization of irAEs in randomized controlled trials biota should be assessed247. Determining the influence is the use of CTCAE88 as these criteria can be difficult to of non-​gastrointestinal microbiota and whether irAEs apply and do not allow accurate reporting of the sever- are influenced by microbial composition and other ity and effect of some irAEs, such as rheumatic or sys- environmental or geographical factors is critical166. temic irAEs88. In addition, many randomized controlled trials only report adverse events of grade 3 or higher Future cancer immunotherapies and exclude those with lower severity27. One study has Newer-​generation cancer immunotherapies and com- underlined the critical challenges in assessing the occur- bination therapies will probably be associated with an rence, type, timing and severity of irAEs, showing a poor enhanced prevalence of irAEs2. Combinatorial ther- inter-​observer agreement for most organ-specific​ irAEs apies using pembrolizumab and avelumab with the (except hypothyroidism)244. multi-​tyrosine kinase inhibitor axitinib were approved Some data from large databases such as the Vigibase145 in late 2019 for the treatment of advanced renal cell car- or the ICIR-​BIOGEAS Registry4 have begun to show a cinoma, with hypothyroidism (25–35%) and arthralgias potential organ-​driven clustering of irAEs. Although (18–20%) being the most frequently reported irAEs248,249. >95% of irAEs are reported as single-organ​ auto­immune In addition, the Janus kinase inhibitor tofacitinib diseases, there is probably some publication bias, espe- enhances the delivery of antibody-​based therapeutics cially in cases reported in randomized controlled tri- to tumour cells through modulation of inflammatory als and pharmacovigilance studies in which irAEs are cells in a mouse model250 and could serve as a ration- always counted as single-organ​ effects. However, a spe- ale for conducting trials in which short-term​ tofacitinib cific cluster of phenotypic associations among muscular is administered with ICIs. In addition, other forms of irAEs (for myositis, myocarditis and myasthenia gravis) immunotherapy, such as those targeting B cells and ther- has been reported, particularly for the co-​existence of apies targeting innate immunity including natural killer myositis and myocarditis (which overlap in one-​third cells, are gaining interest2. New bi-​specific antibodies, of reported cases)226, whereas rheumatic and systemic alternate antibody-​based structures (which target mul- irAEs may be clustered into five differentiated clinical tiple tumour and immune components simultaneously phenotypes4. Future potential applications of artificial and could selectively enhance localized, tumour-targeted​ intelligence in cancer care and research must develop immune activity), and dual immunomodulators (target- worldwide cancer networks and registries that investi- ing inhibitory PD-1 and LAG-3 or targeting stimulatory gate differential presentations and outcomes of irAEs OX40 and inhibitory CTLA-4) are also on the horizon. according to individual, environmental or drug-​related As chimeric antigen receptor T cell therapies become factors242. more widely used for cancer treatment, it is likely that these therapies will be tested in future trials in com- Understanding environmental modulation bination with ICIs. Chimeric antigen receptor T cell One rapidly expanding field is the effect that micro- therapies have been shown to induce toxicities such as biota composition has on the efficacy and toxicity of the cytokine-​release syndrome (characterized by high ICIs180. Understanding the effect of the microbiome on fever, hypotension and multi-​organ toxicity) and chi- the immune response will be essential in enabling the meric antigen receptor T cell-​related encephalopathy treatment of dysbiosis and to re-establish​ equilibrium of syndrome (characterized by symptoms of confusion and the protective gut microflora to limit and treat irAEs. The delirium, seizures and cerebral oedema)251. first irAE in which a key effect of microbiota composi- As different routes of immunotherapy administra- tion has been reported is colitis, where patients with high tion can influence their toxicity profile, with increasing levels of the Bacteroidetes phylum have a decreased risk interest in intra-​tumoural therapies, it will be impor- of colitis11. In addition, the use of adjunctive ‘oncomi- tant to know whether more localized immunotherapies crobiotics’ has been proposed to indirectly promote affect the frequency and severity of triggered irAEs. To beneficial immune responses through optimizing the minimize off-​tissue effects, delivery systems have been gut microbiome245. The first case series of successful designed for local and sustained release in vivo, and many treatment of ICI-associated​ colitis with faecal micro­biota systems, including nanoparticles, scaffolds, hydrogels and transplantation has been reported, with reconstitution cells, can be loaded with multiple therapeutic agents that of the gut microbiome and a relative increase in the are chosen on the basis of targets identified in patient

proportion of Treg cells in the colonic mucosa, lending biopsy samples, although whether these systems reduce further support to the hypothesis that alterations in the the development of irAEs requires further study252. microbiota are involved in ICI-associated​ colitis246. More Published online xx xx xxxx than 200 faecal microbiota transplantation clinical trials

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