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

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.