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Neoadjuvant Pepinemab with Immune Checkpoint Blockade Remodels the Tumor Microenvironment in Metastatic Melanoma

ABSTRACT: Neoadjuvant immune checkpoint inhibitors (ICIs) improve event-free survival in metastatic melanoma, yet resistance and recurrence remain common. We evaluated pepinemab, a Semaphorin 4D (SEMA4D)–blocking antibody, in combination with nivolumab and/or ipilimumab in a phase II neoadjuvant biomarker trial for patients with resectable metastatic melanoma. Patients received two neoadjuvant doses followed by curative-intent surgery and one year of adjuvant nivolumab. Pepinemab-containing regimens did not increase immune-related adverse events and did not delay or preclude curative-intent surgical resection. Mechanistically, pepinemab plus ICI was associated with immune remodeling features, including increased T and B cell infiltration and enrichment of type 1 conventional dendritic cells. These changes were associated with the formation of mature lymphoid aggregates resembling tertiary lymphoid structures that contained clonally expanded T cell receptor repertoires, consistent with localized cytotoxic activity. Together, these findings support further evaluation of SEMA4D blockade as a strategy to enhance neoadjuvant immunotherapy in melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE332987 | GEO | 2026/08/20

REPOSITORIES: GEO

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