A biomarker-driven pilot study with first-in-class treatment shows how targeting SEMA4D may help immune cells organize inside melanoma tumors and work more effectively with immunotherapy.
An experimental drug combination given before melanoma surgery may help immune cells do more than enter a tumor. It may help them organize and work together.
Researchers at Winship Cancer Institute of Emory University in collaboration with scientists at Vaccinex, Inc. studied pepinemab, a first-in-class antibody developed by the company, with the immune checkpoint inhibitors nivolumab, ipilimumab or both. The trial involved 38 patients with stage III melanoma that could be removed surgically. The findings are published in Nature Communications.
The study found that treatment combinations containing pepinemab were associated with broad changes in the tumor’s immune environment. Researchers saw organized groups of T cells, B cells and other immune cells that resembled immune command centers inside or near the tumor. These structures are believed to help immune cells recognize cancer and coordinate an attack.
The study’s co-first authors are Ayana T. Ruffin, PhD, MS, a postdoctoral fellow in the Paulos laboratory at Winship, and Crystal L. Mallow, BS, a senior research scientist at Vaccinex. Ruffin’s work was supported by a Cancer Research Institute Irvington Postdoctoral Fellowship to Promote Racial Diversity and a Winship Postdoctoral Scholar Award.
Taking the Brakes Off and Organizing the Response
Checkpoint inhibitors release molecular “brakes” that can keep T cells from attacking cancer. These drugs have improved outcomes for many patients with melanoma, but some tumors do not respond and others later return.
Pepinemab blocks a protein called semaphorin 4D, or SEMA4D, which affects how immune cells move, communicate and function around a tumor. The researchers wanted to learn whether blocking SEMA4D could make the tumor environment more supportive of an immune response and complement checkpoint inhibitors.
Thirty-two patients received two doses of treatment before surgery in one of four groups: pepinemab with nivolumab, pepinemab with ipilimumab, with all three drugs, or with nivolumab alone. In an additional cohort, six patients proceeded directly to surgery. Everyone who received presurgical treatment underwent the planned operation without a treatment-related delay. No grade 4 or 5 adverse events occurred during treatment before or after surgery.
Immune Cells Form Organized Hubs
The trial was designed to examine biological changes inside the tumors, not to determine whether the combination improved survival, and the study met its primary goal. Tumors from patients who received pepinemab-containing regimens showed signs of improved antigen presentation, the process immune cells use to respond to a threat, along with changes that could help recruit immune cells into the tumor.
Compared with nivolumab alone, pepinemab with nivolumab was associated with greater movement of T cells into the tumor. Researchers also found organized immune-cell clusters resembling tertiary lymphoid structures. Tumors with more mature clusters were associated with longer periods without recurrence of cancer, and some of the most developed structures appeared in tumors from patients who received all three drugs.
Because the treatment groups were small and patients were not randomly assigned, these clinical findings are exploratory. The study does not definitively show that pepinemab improved response rates, prevented recurrence or extended survival. Larger, controlled trials will be needed.
Gregory B. Lesinski, PhD, MPH, associate director for basic research and shared resources at Winship and professor and vice chair for basic research in the Department of Hematology and Medical Oncology at Emory University School of Medicine, says the results broaden the view of why some tumors resist immunotherapy.
“Resistance to checkpoint blockade is not simply a problem with T cells,” Lesinski says. “Our findings suggest that targeting the semaphorin 4D signaling pathway may modify the broader immune ecosystem of patient tumors and improve the quality of the antitumor immune response.”
A Winship and Vaccinex Team Effort
The study grew from a collaboration of more than eight years between Winship and Vaccinex. Vaccinex developed and provided pepinemab and contributed research support, study oversight, data collection, laboratory analysis and manuscript preparation.
Michael C. Lowe, MD, MA, melanoma disease team lead at Winship and professor in the Division of Surgical Oncology of the Department of Surgery at Emory University School of Medicine, led the clinical trial. Laboratory studies were conducted through the laboratories of Lesinski and Chrystal M. Paulos, PhD, director of translational research for cutaneous malignancies and co-leader of the Cancer Immunology Research Program at Winship and professor in the Departments of Surgery and Microbiology and Immunology at Emory University School of Medicine. Paulos, Lowe and Lesinski jointly supervised the work. The Vaccinex research leaders included Elizabeth Evans, PhD, senior vice president of discovery and translational medicine, and Crystal Mallow, senior research scientist, who developed novel immunohistochemical methods for this study.
The project also used four Winship shared resources supported by the NCI Cancer Center Support Grant: Integrated Genomics, Flow Cytometry, Cancer Tissue and Pathology, and Biostatistics. Other Emory contributors included Keith A. Delman, MD, Melinda L. Yushak, MD, MPH, David Lawson, MD, Douglas C. Parker, MD, PhD, Jeffrey M. Switchenko, PhD, Megen C. Wittling, Jacklyn Hammons and Jayden Kim. Researchers at The University of Texas MD Anderson Cancer Center also contributed to the study.
Carrying Forward Brian Olson’s Work
The publication honors the late Brian M. Olson, PhD, a former Emory faculty member who helped establish the framework for the research as it moved into a human clinical trial. Olson died unexpectedly in 2023.
“Brian was a remarkably talented scientist who brought genuine passion and enthusiasm to this work and its potential impact for patients,” Lesinski says. “Completing the study is a meaningful tribute to someone deeply admired by his collaborators at Emory, Vaccinex and beyond.”
Next Steps for this Research
Researchers plan to study the approach in larger, controlled trials to learn whether the immune changes lead to better responses, fewer recurrences or longer survival. They also want to determine which patients may be most likely to benefit and whether the same approach could work in other solid tumors or with other forms of immunotherapy.
The investigator-initiated trial was sponsored by Emory University and Winship Cancer Institute. Research reported in this publication was supported by the National Cancer Institute and the National Institutes of Health under grant numbers R01CA300792 and P30CA138292. Vaccinex provided pepinemab and research support, and Bristol Myers Squibb provided nivolumab and ipilimumab.
