EXTH-119. Targeting myddosome signaling to improve immunotherapy in melanoma brain metastases

Abstract BACKGROUND Melanoma brain metastases (MBM) develop in up to 60% of patients with metastatic melanoma (MM) and are a major driver of mortality. First-line treatment typically includes immune checkpoint blockade (ICB) with anti-PD-1 and anti-CTLA-4, often combined with surgical resection or stereotactic radiosurgery. However, the brain remains a frequent site of treatment resistance, due to limited blood-brain barrier (BBB) penetrance of therapeutics, poor tumor lymphocyte (TIL) infiltration, and the presence of immunosuppressive tumor-associated myeloid cells (TAMs). We recently identified increased activation of the myddosome signaling pathway in TAMs within MBM, suggesting a mechanistic basis for their suppressive phenotype. IRAK-4, a critical downstream effector of MyD88, represents a potential target for TAM reprogramming. We have shown that the IRAK-4 inhibitor emavusertib (CA-4948), an oral small molecule, crosses the BBB and achieves therapeutic levels in the brain. We hypothesize that emavusertib can alleviate myeloid cell–mediated immune suppression, thereby enhancing the response to ICB in MBM. METHODS Single-cell RNA sequencing of MM and MBM patient samples was used to assess myddosome activation. Preclinical melanoma models (cutaneous and intracranial) were treated with emavusertib alone or in combination with anti-PD-1 ICB. Tumor burden and survival were assessed. Immune responses were evaluated using flow cytometry, immunohistochemistry, and cytokine profiling in tumor tissue and cerebrospinal fluid. RESULTS Myddosome signaling was elevated in TAMs from MM samples, including MBM. Emavusertib reduced myeloid-derived immunosuppressive cytokines and decreased recruitment of peripheral TAMs. Combination treatment with emavusertib and anti-PD-1 significantly reduced tumor growth and improved survival across three models. Increased lymphocyte infiltration and IFNγ expression indicated enhanced antitumor immunity. CONCLUSION Targeted IRAK-4 inhibition with emavusertib reprograms suppressive TAMs and enhances response to anti-PD-1 therapy in MBM models. These findings support emavusertib as a promising adjuvant to ICB in MM, providing the foundation for a first in human clinical trial (NCT05669352).