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.