PD-1 inhibitor therapy causes multisystem immune adverse reactions: a case report and literature review

Abstract

Immune checkpoint inhibitors(ICIs), including cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) inhibitors, have been shown to have antitumor activity in various solid tumors. Their mechanism of action is to selectively restore and normalize the body’s immune reponses by disrupting the immunosuppressive signals mediated by PD-1, PD-L1 and CTLA-4 in the tumor microenvironment. With the increase in clinical applications of ICIs, reports of immune-related adverse events (irAEs) have also increased. This article reports a case of a lung cancer patient who developed multisystemic adverse effects after PD-1 inhibitor application: myocarditis, myositis and thrombocytopenia, and analyzes the role of Interleukin 6(IL-6)in the management of irAEs. Despite the patient’s eventual discontinuation of antitumor therapy due to severe irAEs, a significant and durable therapeutic response was observed.

Mediators and mechanisms of immune checkpoint inhibitor‐associated myocarditis: Insights from mouse and human

“…Broad markers of inflammation such as C reactive protein (CRP) are often increased, 63–65 though the diagnostic value of such nonspecific markers is limited. Elevated serum levels of the pro‐inflammatory cytokine IL‐6 have been reported by multiple groups, though the source of the cytokine and the cardiac response have not been clarified 63,64,66,67 . Measurement of IL‐6 levels may contribute to irMyocarditis diagnosis, as its elevation in serum conferred a sensitivity of 100% and specificity of 71% 66 .…”

“…Indeed, whether IL‐6 functions as a pathophysiologic mediator in irMyocarditis remains unclear, though the use of tocilizumab, a monoclonal antibody specific for the IL‐6 receptor, as part of a successful irMyocarditis treatment regimen has been reported 70–72 . Multiple other cytokines including IL‐8, IL‐10, CXCL9, CXCL10, CXCL12, CXCL13, and VEGF‐A may also increase during irMyocarditis, but a systematic analysis including controls with cancer and exposed to ICIs has not yet been reported 63,64,66,67 …”

“…Elevated serum levels of the pro-inflammatory cytokine IL-6 have been reported by multiple groups, though the source of the cytokine and the cardiac response have not been clarified. 63,64,66,67 Measurement of IL-6 levels may contribute to irMyocarditis diagnosis, as its elevation in serum conferred a sensitivity of 100% and specificity of 71%. 66 These values, however, were calculated when comparing irMyocarditis patients to healthy controls (i.e., without cancer and without exposure to ICIs, both of which can alter circulating cytokine levels 68,69 ); as such, this analysis should best be considered hypothesisgenerating.…”

“…[70][71][72] Multiple other cytokines including IL-8, IL-10, CXCL9, CXCL10, CXCL12, CXCL13, and VEGF-A may also increase during irMyocarditis, but a systematic analysis including controls with cancer and exposed to ICIs has not yet been reported. 63,64,66,67 Owing mainly to the difficulty of obtaining fresh human heart tissue, only four studies have directly studied such tissue from patients with irMyocarditis 20,47,73,74 ; two have employed bulk RNA sequencing to identify genes and pathways that are differentially expressed in irMyocarditis. 73,74 The first report of gene expression changes in irMyocarditis used a panel of 579 genes involved in immune responses to compare transcript expression from irMyocarditis heart samples relative to liver and lung metastasis samples from the same patient.…”