Neurotoxicity in immune checkpoint inhibitor-associated myositis with elevated soluble IL-2 receptor levels: Novel therapeutic strategies.

e14536 Background: Immune checkpoint inhibitors (ICIs) are used to treat a variety of cancer types, including melanoma, lung cancer, and breast cancer. Approximately 1-5% of patients receiving ICIs develop neurotoxicity (N-TOX). N-TOX is driven by a loss of immune tolerance, leading to aberrant activation of T-cells, astrocytes, and microglia. There is a need to better understand the pro-inflammatory milieu in N-TOX to facilitate novel treatment strategies for treatment. Therefore, we performed a retrospective review in a single institution in patients who developed N-TOX to better understand this patient population. Methods: We conducted a retrospective study of cytokine samples (CSF and/or serum) from 33 patients who developed N-TOX after ICI therapy at Moffitt Cancer Center between 2023 and 2025. Cytokine-13 panels (ARUP Laboratories, Utah) were obtained in serum only (N = 15), CSF only (N = 13), or both serum and CSF (N = 5). Results: Primary cancer types were melanoma (N = 9), lung (N = 5), renal (N = 3), head/neck (N = 3), thyroid (N = 2), urothelial, cervical, endometrial (N = 1), Merkel cell, penile, appendiceal, breast, sarcoma, liver, esophageal, and gastric (all N = 1). N-TOX syndromes included myositis (N = 17), encephalitis (N = 9), neuropathy (N = 8), myasthenia gravis (N = 2), meningitis (N = 1), and demyelinating disease (N = 1). In our cohort group, serum cytokine analysis demonstrated elevated IL-10 (10.7 +/- 5.6 pg/ml, reference < 2.8 pg/ml, p = 0.003) without significant changes in other serum cytokines. Of note, 80% of serum cytokines were collected after initiation of steroids. CSF cytokine analysis did not demonstrate any significant elevation in cytokine levels. Subgroup analysis of N-TOX myositis patients showed a significant elevation in serum sIL2R (1203 +/- 307 pg/ml, reference 175-858 pg/ml, p = 0.024) without elevation in serum interferon gamma. Subgroup analysis of N-TOX neuropathy and N-TOX encephalitis patients did not show any significant elevation in serum or CSF cytokine levels, respectively. Conclusions: Serum sIL2R was elevated in selected N-TOX patients with myositis, which suggests that therapeutic strategies to influence this cytokine or its downstream substrates may be effective. We are currently undertaking a prospective cohort with muscle biopsies to better understand this association. The serum IL-10 elevation is an anti-inflammatory response likely confounded by treatment effect.