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.