Plasma Cytokine Levels in Patient with Multiple Immune-Related Adverse Events During Nivolumab Therapy for Metastatic Cutaneous Melanoma

Abstract

Nivolumab, like other immune checkpoint inhibitors, is effective in the treatment of malignant neoplasms. However, there is a growing number of reports describing the development of immune-related adverse events associated with cytokine imbalance, including myocarditis, pericarditis, pneumonitis, myositis, joint involvement, intestinal lesions, and thyroiditis, characterized by spontaneity and a reactive course. It has been hypothesized that such events are related to the disinhibition of the immune system and the development of inflammation via an autoimmune mechanism, involving the patient’s own healthy tissues and organs due to cross-reactivity in the setting of cytokine imbalance.

We observed a 65-year-old woman over a 4-year period, beginning in 2019, when she first presented with complaints of a bleeding pigmented lesion on the right lower leg, later classified as cutaneous pigmented melanoma (nodular type, with ulceration and mitotic activity). She remained under observation for 2 years, and in 2021, following disease progression, she underwent 7 cycles of nivolumab therapy. Shortly thereafter, the patient reported a deterioration in her condition. From August 2021 to early 2022, she developed acute myocarditis and pericarditis, pneumonitis, myositis, a hematologic syndrome, skin induration of the extremities, and polyneuropathy. The patient was hospitalized in the rheumatology department.

Researchers from the scientific department conducted a plasma cytokine study to determine the levels of several cytokines previously found to be elevated in patients with autoimmune diseases. Plasma analysis revealed increased levels of interleukin-1β, MIG, PDGF-AB/BB, RANTES, and TGF-α. These findings indicated an intermediate type of inflammatory response: less controlled than in patients without adverse effects but not reaching the level of autoimmune inflammation observed in rheumatoid arthritis.

A hypothesis was proposed regarding the development of a hybrid inflammatory process, combining a systemic component of the oncologic disease and hyperactivation of the Th17 response, with a predominance of proinflammatory mediators’ characteristic of autoimmune pathologies. Nivolumab was discontinued, and comprehensive therapy was initiated to manage the cardiologic, neurologic, and rheumatic complications. Remission of the primary disease (melanoma) was achieved.

Keywords

clinical case / oncology / melanoma / immune checkpoint inhibitors / nivolumab / PD-1 / cardiomyopathy

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Funding

Правительство Российской ФедерацииGovernment of the Russian Federation(075-03-2024-642)

Правительство Российской ФедерацииGovernment of the Russian Federation(075-00264-24-00)

RIGHTS & PERMISSIONS

Khizha V.V., Kozlova D.I., Sholokhov G.V., Kuzin S.O., Khaimanova D.G.