Neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in resectable metastatic melanoma: a pilot biomarker-driven trial
Abstract
Neoadjuvant immune checkpoint inhibitors (ICIs) improve event-free survival in metastatic melanoma, yet resistance and recurrence remain common. Here we evaluated pepinemab, a Semaphorin 4D (SEMA4D)–blocking antibody, in combination with anti-PD1 nivolumab and/or anti-CTLA4 ipilimumab in a pilot biomarker-driven neoadjuvant trial (NCT03769155) for patients with resectable metastatic melanoma. The primary endpoint was to determine if pepinemab combined with ICIs modulates phenotypic properties within the tumor microenvironment in a manner that enhances T effector cell infiltration. Secondary endpoints included safety and tolerability, pathological response rates and radiographical response. Patients received two neoadjuvant doses followed by curative-intent surgery and one year of adjuvant nivolumab. Pepinemab-containing regimens demonstrated manageable toxicity profiles and did not delay or preclude curative-intent surgical resection in the 38 patients treated. The trial met its primary endpoint, as enrichment of transcripts associated with activated dendritic cells and immune recruitment pathways was observed in tumors from patients receiving pepinemab-containing regimens. Further, immune remodeling was evident by formation of mature lymphoid aggregates resembling tertiary lymphoid structures that contained clonally expanded T cell receptor repertoires. While this study was not powered to assess clinical efficacy, our findings do support further evaluation of SEMA4D blockade as a strategy to modulate the tumor microenvironment and potentially augment immunotherapy in melanoma and other solid malignancies.
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BibTeX
@article{ruffin2026neoadjuvant,
title = {{Neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in resectable metastatic melanoma: a pilot biomarker-driven trial}},
author = {Ayana T. Ruffin and Crystal L. Mallow and Brian M. Olson and Jacklyn Hammons and Brenda Melendez and Manoj Chelvanambi and Elaine M. Gersz and Megen C. Wittling and Laurence P. Diggs and Christine Reilly and Jeffrey M. Switchenko and Alexander J. Lazar and Shannon K. Swisher and Jayden Kim and Brian Burns and Agnes Harutyunyan and Terrence L. Fisher and Keith A. Delman and Melinda L. Yushak and Douglas C. Parker and David Lawson and Jennifer A. Wargo and Maurice Zauderer and Elizabeth E. Evans and Chrystal M. Paulos and Michael C. Lowe and Gregory B. Lesinski},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78231-3},
url = {https://www.nature.com/articles/s41467-026-78231-3},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in resectable metastatic melanoma: a pilot biomarker-driven trial
AU - Ayana T. Ruffin
AU - Crystal L. Mallow
AU - Brian M. Olson
AU - Jacklyn Hammons
AU - Brenda Melendez
AU - Manoj Chelvanambi
AU - Elaine M. Gersz
AU - Megen C. Wittling
AU - Laurence P. Diggs
AU - Christine Reilly
AU - Jeffrey M. Switchenko
AU - Alexander J. Lazar
AU - Shannon K. Swisher
AU - Jayden Kim
AU - Brian Burns
AU - Agnes Harutyunyan
AU - Terrence L. Fisher
AU - Keith A. Delman
AU - Melinda L. Yushak
AU - Douglas C. Parker
AU - David Lawson
AU - Jennifer A. Wargo
AU - Maurice Zauderer
AU - Elizabeth E. Evans
AU - Chrystal M. Paulos
AU - Michael C. Lowe
AU - Gregory B. Lesinski
PY - 2026
DA - 2026/10/06
JO - Nature Communications
DO - 10.1038/s41467-026-78231-3
UR - https://www.nature.com/articles/s41467-026-78231-3
AB - Neoadjuvant immune checkpoint inhibitors (ICIs) improve event-free survival in metastatic melanoma, yet resistance and recurrence remain common. Here we evaluated pepinemab, a Semaphorin 4D (SEMA4D)–blocking antibody, in combination with anti-PD1 nivolumab and/or anti-CTLA4 ipilimumab in a pilot biomarker-driven neoadjuvant trial (NCT03769155) for patients with resectable metastatic melanoma. The primary endpoint was to determine if pepinemab combined with ICIs modulates phenotypic properties within the tumor microenvironment in a manner that enhances T effector cell infiltration. Secondary endpoints included safety and tolerability, pathological response rates and radiographical response. Patients received two neoadjuvant doses followed by curative-intent surgery and one year of adjuvant nivolumab. Pepinemab-containing regimens demonstrated manageable toxicity profiles and did not delay or preclude curative-intent surgical resection in the 38 patients treated. The trial met its primary endpoint, as enrichment of transcripts associated with activated dendritic cells and immune recruitment pathways was observed in tumors from patients receiving pepinemab-containing regimens. Further, immune remodeling was evident by formation of mature lymphoid aggregates resembling tertiary lymphoid structures that contained clonally expanded T cell receptor repertoires. While this study was not powered to assess clinical efficacy, our findings do support further evaluation of SEMA4D blockade as a strategy to modulate the tumor microenvironment and potentially augment immunotherapy in melanoma and other solid malignancies.
SN - 2041-1723
ER -