Introduction
Immune checkpoint inhibitors have proven to be a promising and novel therapy for a variety of previously refractory malignancies, designed to subvert the cancer-mediated suppression of the normal immune system. Malignancies can adapt to the host environment, exacting a number of signaling cascades to evade host detection. Malignant cells can limit recognition by downregulation of the major histocompatibility complex (MHC) Class I molecules involved in antigen presentation to T-lymphocytes and modulate the tumor microenvironment by dampening regulatory T-lymphocytes (Treg), myeloid-derived suppressor cells, and tumor-associated macrophages via elaboration of multiple immunosuppressive soluble cytokines (TGF-ß, IL10).1-5Additionally, malignant cells suppress host immune activation by upregulation of specific cell-surface proteins such as Programmed Death Ligand 1 (PD-L1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) – whose ultimate function is to bind to receptors on those inflammatory, tumor-killing, tumor-infiltrating T-lymphocytes and block pathways associated with T-lymphocyte activation, proliferation, in turn limiting malignant cell detection and killing.6-8While many factors play a role in mediating effective immune responses to cancer, T-lymphocytes are a cornerstone of the anti-cancer immune response and are likely a critical factor in determining clinical outcome.
T-lymphocytes target tumor cells mainly by two mechanisms. The first mechanism involves an antigen-specific signal through T-cell receptors (TCRs); the second mechanism involves antigen-nonspecific signals mediated by co-signaling receptors: co-stimulatory or co-inhibitory, which act by accentuating or attenuating T-lymphocyte responses, respectively.9,10 CD28 is an important co-stimulatory receptor, whereas CTLA-4 and PD-1 are co-inhibitors. These latter signals are essential to restrict cytotoxic T-lymphocyte effector function. Malignancy-mediated upregulation of PD-L1 and CTLA4 leads to T-lymphocyte anergy and suppression, ultimately leading to evasion of the host immune response. It was subsequently hypothesized that blockade of the PD-1/ PD-L1 interaction or inhibition of the malignancy-mediated upregulation of PD-L1 and CTLA4, would lead to enhanced recognition of malignant cells. Backed by strong pre-clinical evidence, these novel therapies have proven to be very effective in advanced melanoma in phase I-III trials.11-13 Two such therapeutics, Nivolumab and Ipilimumab, designed to inhibit PD-1 and CTLA-4, respectively, have steadily expanded their application from advanced melanoma to a variety of other advanced malignancies, including renal cell carcinoma, colorectal cancer, non-small-cell lung cancer.12-18
While these immunotherapies have demonstrated enhanced tumor recognition and T-lymphocyte activation, their use has been associated with several deleterious side effects, termed immunotherapy-related adverse events (irAEs). Though the exact pathogenesis of irAEs remains to be fully delineated, it is thought to be driven by the same immunologic mechanisms responsible for the drugs’ therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unchecked acute or chronic immune response.19 Though a variety of irAEs have been described in the literature – colitis, thyroid dysfunction, pneumonitis, hepatitis, and nephritis – cardiac involvement has been noted to be exceedingly rare, with an incidence rate of less than 1%, and commonly manifests as non-specific symptoms - dyspnea, palpitation, fatigue, and myalgia.20-24 Here we report a case of dual-immunotherapy associated myopericarditis in an individual with metastatic renal cell carcinoma treated with combinatorial Nivolumab/ Ipilimumab therapy and provide a brief literature review regarding the biological mechanisms of immunotherapy and the pathophysiology behind irAEs.