Immunotherapy-related adverse effects (irAEs)
Immune checkpoint molecules play a critical role in maintaining immune tolerance and prevent unnecessary damage from excessive activation, involving several different mechanisms. Numerous studies have demonstrated that deficiency or reduced expression of CTLA-4 or PD-1 leads to uncontrolled T-lymphocyte proliferation, autoimmunity, multiorgan failure, and early death.63-67 The incidence of irAEs depends on several factors including the type of ICI, dosage, monotherapy or combined therapy, and the cumulative dosage.68 According to a meta-analysis synthesized from 22 clinical trials, irAEs cover a broad spectrum across all organ-systems, most commonly manifesting as - dermatologic (eg. vitiligo and self-limited dermatitis), gastrointestinal (eg. Colitis), endocrine (eg. hypothyroidism, hyperthyroidism, type 1 diabetes), hepatitis, and pulmonary (eg. Pneumonitis) manifestations.12,69 In histopathological findings from the ICI-mediated irAE vitiligo patients, CD4 and melan-A-specific CD8 T-lymphocytes were found juxtaposed to apoptotic melanocytes.70 Similarly, T-lymphocyte infiltration was found in other common irAEs, indicating that ICIs stimulated an immune response directed against normal cells leading to the noted multi-organ irAEs (e.g. colitis, pancreatitis, and endocrinopathies).71,72 ICI-mediated myocarditis and pericarditis are less commonly reported, though can be fatal.73,74 Previously published data from animal models and case reports have demonstrated the presence of lymphocytic infiltration of the myocardium and pericardium,65,74-76 with immunohistochemical analysis revealing the presence of markers for T-lymphocytes (CD3, CD4, CD8, and FOXp3), B-lymphocytes (CD20), macrophages (CD68), PD-L1, and diffuse IgG and complement deposition (C3d, C4d).65,76 In a PD-1 deficient mouse model, Nishimura et al. found cardiac-specific autoantibodies.65 Taken together, these findings suggest that ICI-mediated myocarditis may result from a common, shared antigen between malignant cells and cardiac myocytes, homologous tumor and myocardial antigens, or dissimilar antigenic targets with shared epitopes.74 Further research is warranted to investigate the exact mechanism and variability not only in incidence but the variable patterns of irAEs, even in the context of similar background malignancies in patients treated with ICIs.
The American Society of Clinical Oncology (ASCO) published guidelines in 2018 to aid in the diagnosis and workup of suspected cardiotoxicity secondary to immunotherapy.77 These guidelines note that diagnostic evaluation include an ECG, troponin, NT-pro-BNP, and echocardiogram, as well as viral serologies, to exclude alternative causes of cardiac myocyte inflammation.77 In a large series, ECG abnormalities were noted in 89% of cases, troponin elevations were present in 94% of cases, and echocardiogram was characteristic of a normal LVEF in 51% of cases.78The severity of myocarditis can furthermore be subclassified into four grades (Table 2 ), with the management tailored to the grade; those with Grade 2 or above require high-dose steroid therapy, whereas those with Grade 4 require aggressive immunosuppression and oftentimes, adjunctive advanced heart failure supportive therapies.77 Escudier and colleagues published a descriptive observational analysis of 30 patients with ICI-related cardiotoxicity and noted that, not surprisingly, management ought to be individualized according to cancer status and the presence of toxicity regression.79 They furthermore noted that corticosteroid use correlated with improved left ventricular function, and cardiotoxicity did not reoccur in those who underwent ICI administration.79
Despite the noted deleterious and potentially serious side effects of ICIs, the development and severity of irAEs appeared to be associated with a clinical benefit, according to a recently unpublished study involving 124 patients with advanced sarcoma.80 In this study, Rosenbaum and colleagues found that in comparison to those patients that developed an irAE, those patients without irAEs, not only had a decreased response to ICI therapy (6% v. 18%), but also had a lower clinical benefit (29% v. 53%) as well as a decreased median progression-free survival (10.6 v. 16.4 weeks).80Furthermore, when comparing patients with lower grade irAEs (Grade 1-2) or no irAEs to those patients with higher grade irAEs (grade 3-4), the patients in the higher grade irAE group were noted to have a significantly increased response rate (33% v. 15% v. 6%), a higher durable clinical response (67% v. 50% v. 29%), and a longer median progression-free survival (22.6 v. 15 v. 10.6 weeks).80
Our patient presented with a constellation of symptoms; with. his initial shortness of breath aptly and quickly attributed to an irAE in the setting of his ICI therapy for his renal cell cancer, and he was promptly initiated on high dose steroids. His presenting laboratory diagnostics demonstrated mild transaminitis, hyperthyroidism, and an elevated CK and troponin. Diagnostic imaging demonstrated the presence of a persistent mass abutting the SVC, however physical examination demonstrated no evidence of SVC syndrome and IV hydration failed to improve his symptomatology. Furthermore, while he had a prior history of radiation, the temporal relationship between the onset of his immunotherapy and symptoms made radiation-induced injury less likely.81 As such it appears that he presented with a mild systemic inflammatory response secondary to ICI therapy, which subsequently responded to steroid therapy. He was ultimately diagnosed with Grade 2 myocarditis given his mild symptoms and lab abnormalities. Though the exact pathophysiological mechanism remains unknown, it is likely that in this case ICI therapy resulted in a down-regulation of the normal immune-regulatory signaling mediated by CTLA-4 and PD-1, with resultant cross-reactivity of malignancy-associated antigens with antigens on healthy myocytes. In the ideal environment, regulatory T-lymphocytes would ordinarily recognize the healthy cell antigen and suppress the immune response, however in the setting of ICI therapy, these normal regulatory events are abrogated. As the patient’s symptoms returned with cessation of steroids, we suspect that the patient’s presentation was driven by the development of an autoimmune response with associated autoantibody production. Alternatively, his presentation may also be explained by IgG and complement deposition, as suggested in Nishimura’s study, which has been suggested to play a role in the recurrence of symptoms.65 This would place our patient in a different subset of patient’s who develop irAEs, as this implicates involvement of the adaptive immune system and development of memory and effector T-lymphocytes.
Our patient also presented with thyrotoxicosis. Immune-related thyroiditis usually manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The incidence of immune-related thyroiditis is notably higher and occurs with increased rapidity in those treated with a combination of ICI, warranting frequent monitoring of thyroid function tests. Our patient had routine follow up with his oncologist for close monitoring of thyroid function tests and subsequent initiation of levothyroxine supplementation.