Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors—an autopsy study

Abstract

BackgroundImmune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have been recently approved for treatment of patients with metastatic melanoma and non-small cell lung cancer (NSCLC). Despite important clinical benefits, these therapies are associated with a diverse spectrum of immune-related adverse events (irAEs) that are typically transient, but occasionally severe or even fatal.Case presentationThis autopsy case illustrates that clinically overt irAEs may represent only a fraction of the total spectrum of immune-related organ pathology in patients treated with immune checkpoint inhibitors. We report a comprehensive analysis of systemic irAE pathology based on the autopsy of a 35-year-old female patient with metastatic melanoma treated first with ipilimumab and then nivolumab. The clinical course was characterized by a mixed tumor response with regression of skin and lung metastases and fatal progression of metastatic disease in the small bowel, peritoneum and brain. During therapy with ipilimumab, radiographic features of immune-related pneumonitis were noted. The autopsy examination established a sarcoid-like granulomatous reaction of the lung, pulmonary fibrosis and diffuse alveolar damage. Importantly, a clinically unapparent but histologically striking systemic inflammation involving the heart, central nervous system, liver and bone marrow was identified. Severe immune-related end-organ damage due to lymphocytic myocarditis was found.ConclusionsAutopsy studies are an important measure of quality control and may identify clinically unapparent irAEs in patients treated with immunotherapy. Pathologists and clinicians need to be aware of the broad spectrum of irAEs for timely management of treatment-related morbidity.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0117-1) contains supplementary material, which is available to authorized users.

Sarcoidosis in the setting of combination ipilimumab and nivolumab immunotherapy: a case report & review of the literature

“…To date, sarcoidosis development has been reported in untreated melanoma patients and those managed with interferon, peptide vaccine, vemurafenib, ipilimumab and nivolumab [5–14, 16–21]. To our knowledge, this is the first reported incident of sarcoidosis with combination ipilimumab and nivolumab immunotherapy.…”

Fulminant Myocarditis with Combination Immune Checkpoint Blockade

“…15–18 Our review of a large safety database suggests that myocarditis is more frequent and severe with the combination of ipilimumab and nivolumab compared with nivolumab monotherapy, but remains rare (<1%) with both regimens. Since cardiac monitoring (e.g.…”

Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report

“…These observations suggest an important role of PD-1 in limiting T cell-mediated inflammatory responses in the heart [16]. Other cases of myocarditis and acute heart failure have been reported in cancer patients treated with PD-1 inhibitors [17–19]. However, cardiac toxicity is not a common adverse event associated with this class of agents.…”