Neoadjuvant Pepinemab in Combination with Nivolumab and/ or Ipilimumab in Resectable Stage III Melanoma

INTRODUCTION: SEMA4D regulates myeloid suppression and trafficking in the tumor microenvironment (TME); blocking SEMA4D along with checkpoint inhibitors (CI) promotes immune infiltration and tumor regression. We hypothesized that adding SEMA4D-blocking pepinemab (pepi) to CI may augment T cell mediated immunity and provide clinical benefit in patients with resectable melanoma.

METHODS: Stage IIIB/C/D melanoma patients were treated with pepi/nivolumab (nivo), pepi/ipilimumab (ipi), pepi/nivo/ipi or nivo alone (n=8 each; NCT03769155). Two doses were given three weeks apart; surgery occurred three weeks later followed by adjuvant nivo. Primary clinical endpoint was major pathologic response (pMR), including complete (pCR) and near-pCR. Secondary endpoints were safety, surgical delays, and RFS. High dimensional immune analysis was performed with 32-color flow cytometry. Spatial distribution of immune populations using multiplex IHC was compared between pretreatment and surgical tissue.

RESULTS: All patients safely proceeded to surgery without delay. Rates of pMR in the pepi/nivo, pepi/ipi, pepi/nivo/ipi, and nivo arms were 37.5%, 12.5%, 75.0%, and 42.9%, respectively. Adverse event rates were similar to previous studies of CI regimens not containing pepi. At median follow up of 22 months, all patients receiving pepi/nivo/ipi were recurrence-free. An increase in activated and proliferating CD4+ T cells expressing Ki67 and CD26 was detected in patients receiving pepi. Pepi/nivo/ipi treatment significantly increased tumor-infiltrating B cells and CD4+ T cells, including organized tertiary lymphoid structures (TLS) comprised of high-density B and T cells in the TME. Patients experiencing pMR to pepi/nivo/ipi had increased frequencies of tumor-infiltrating B cells and CD4+CD26hi T cells and elevated M1/M2 macrophage ratio.

CONCLUSIONS: The combination of pepi/nivo/ipi is well-tolerated and provides robust and durable pathologic response. This therapy may act by fostering interactions between B and T cell populations within TLS and modulating myeloid cells. Pepi has the potential to augment the activity of CI in melanoma without additional toxicity.

Authors: Michael C. Lowe, MD, MA, FACS, FSSO, Associate Professor - Emory University (Presenter;Submitter;Author); Brian Olson, PhD, Assistant Professor- Emory University (Author); Melinda Yushak, MD, MPH, Assistant Professor- Emory University (Author); Crystal Mallow, n/a, Investigator- Vaccinex, Inc. (Author); Christine Reilly, n/a, Investigator - Vaccinex, Inc. (Author); Jacklyn Hammons, n/a, Research Specialist - Emory University (Author); Brian Burns, n/a, Investigator - Emory University (Author); Ali Mokhtari, MD, Pathology Resident - Emory University (Author); Doug Parker, MD, Associate Professor - Emory University (Author); Terry Fisher, PhD, Investigator - Vaccinex, Inc (Author); Elizabeth Evans, PhD, Investigator - Vaccinex, Inc. (Author); Chrystal Paulos, PhD, Associate Professor - Emory University (Author); Keith Delman, MD, Professor - Emory University (Author); Gregory Lesinski, PhD, Professor - Emory University (Author)