Immune checkpoint inhibitors have demonstrated efficacy across many cancer types in numerous clinical trials. However, because patients with preexisting autoimmune disease were excluded from these seminal trials, there are serious gaps in knowledge regarding the efficacy—and in particular the safety—of these transformative agents in patients with autoimmune disease. The safety of immune checkpoint inhibitors in this population has been an important concern, since these agents unleash immune activation, a potentially dangerous situation for patients with already heightened and aberrant immune function. Several retrospective studies have begun to address this question, finding that autoimmunity is often exacerbated by immune checkpoint inhibitor therapy, but is generally manageable with standard treatment algorithms and close multidisciplinary monitoring. Further, the activity of these agents appears to be comparable to that seen in unselected patients. Here we detail the experience with immune checkpoint inhibitors in patients with autoimmune disease.
The advent of effective immunotherapy using immune checkpoint inhibitors has transformed the therapeutic landscape for many cancers. Agents targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) unleash key negative regulators of immune activation, thus “removing the brakes” on an effective antitumor immune response. They offer the possibility of previously unheard-of long-term therapeutic benefit for patients with metastatic solid tumors.
Because of the mechanism of action of these therapies, their toxicities are related to aberrant activation of immune cells against self-antigens. These side effects, termed “immune-related adverse events” (irAEs), may affect and inflame essentially any organ. Anti–CTLA-4 antibodies most frequently induce colitis, hepatitis, hypophysitis, thyroiditis, and dermatitis, with severe effects occurring in approximately one-third of patients. Anti–PD-1 agents have similar, albeit less frequent toxicities, and may also cause pneumonitis, inflammatory arthritis, and other adverse effects. Recent studies have also shown that these agents may occasionally cause systemic syndromes that are seemingly identical to known rheumatologic disorders (eg, Sjögren syndrome, sarcoidosis).[3,4] Although these side effects can typically be managed with corticosteroids and other immunosuppressants, highly morbid and even fatal events can occur in a small proportion of patients. Predicting which patients will experiences irAEs and mitigating the risk of severe organ injury remain critical and unmet needs (Figure).
While the molecular characteristics of irAEs are still being unraveled, it is evident that the clinical and histopathologic presentation of these events has a strong resemblance to autoimmune disease. Early insights into their pathogenesis have demonstrated T-cell and macrophage infiltration into the inflamed tissue, as well as autoantibody and antibody-complement deposition in some cases.[5-7] For this reason, it has been of concern that patients with preexisting autoimmune disease would experience flares in their underlying condition when treated with immune checkpoint inhibitors. Further, one could hypothesize that patients prone to autoimmunity might have additional organ inflammation triggered when exposed to this therapy.
An additional source of concern is the fact that there is a wealth of literature documenting the critical role of both CTLA-4 and PD-1 in autoimmunity and in maintaining immune tolerance to self-antigens. Knockout mice designed to genetically lack these molecules develop fulminant and fatal multiorgan autoimmunity (CTLA-4 knockout); or either myocarditis, cardiomyopathy, or a lupus-like syndrome (PD-1 knockout).[10,11] Moreover, CTLA-4 agonists (abatacept, belatacept) are approved for the treatment of various autoimmune diseases. These concerns have led to the exclusion of patients with autoimmune disease from seminal immune checkpoint inhibitor studies. Thus, when facing a patient with active autoimmune disease and metastatic cancer, a clinician is confronted with a significant dilemma, and a lack of prospective data to inform the safety of treatment.
However, subsequent experience has suggested that the relationship between autoimmunity and immunotherapy is not straightforward. The current data regarding this relationship are not derived from large prospective studies, but rather from retrospective series and case reports. Still, they do provide insights for clinicians and can help them with treatment decision making, and with balancing the competing risks of metastatic cancer and autoimmune disorders.
Ipilimumab and Autoimmune Disease
Ipilimumab is approved for use in advanced melanoma at a lower dose (3 mg/kg) and as adjuvant therapy for patients at high risk for recurrence at a high dose (10 mg/kg). Several case reports have suggested that patients with autoimmune disease might tolerate ipilimumab safely and could potentially benefit from therapy.[12,13] To provide additional insights, our group performed a retrospective study of 30 patients with autoimmune disease from 9 centers. These patients had a wide range of diseases, most commonly inflammatory bowel disease (n = 6), rheumatoid arthritis (n = 6), and psoriasis (n = 5). Of these patients, 27% experienced autoimmune exacerbations and 33% had standard irAEs (Table). All of these events were manageable with corticosteroid treatment, infliximab, and/or discontinuation of ipilimumab, except for one patient with pre-existing psoriasis in whom colitis developed and became fatal after a long delay in seeking care. Several patients with inflammatory bowel disease had flares. Half of patients experienced no toxicities and 20% responded to treatment. An additional series of 8 patients with rheumatoid arthritis demonstrated frequent but manageable arthritis flares (25% with grade 3), frequent colitis (50%; all resolved with treatment), and high response rates (50%). From these studies, we conclude that autoimmune disease is not an absolute contraindication to ipilimumab therapy, as long as close clinical monitoring is provided. We would be hesitant, however, to offer high-dose therapy (10 mg/kg), a more toxic regimen, in the adjuvant setting (particularly with the availability of adjuvant nivolumab currently). For patients with more severe autoimmune disease (eg, Guillain Barré syndrome), we would also have an extended discussion of potential life-threatening consequences.
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