Vaccinex's Pepinemab Shows Promise in Turning "Cold" Tumors "Hot" Through Enhanced Immune Response
Key Insights
Vaccinex will present new clinical data at ASCO 2025 showing that neoadjuvant treatment with pepinemab induces mature tertiary lymphoid structures that correlate with improved pathologic response in head and neck cancer patients.
The SEMA4D (search)-blocking antibody pepinemab demonstrates potential to transform immunologically "cold" tumors into "hot" immune centers by enhancing dendritic cell function and T cell interactions within organized immune structures.
Clinical studies reveal that pepinemab combination therapy enhanced tertiary lymphoid structure maturity and correlated with longer recurrence-free survival in metastatic melanoma patients without compounding toxicities.
Vaccinex Inc. is preparing to unveil promising clinical data demonstrating how its lead drug candidate pepinemab can transform immunologically "cold" tumors into responsive treatment targets through a novel mechanism that enhances immune checkpoint therapy effectiveness.
The Rochester-based biotechnology company announced it will present new findings at the 2025 ASCO Annual Meeting in Chicago, revealing that neoadjuvant treatment with pepinemab induces abundant, mature lymphoid structures that correlate with improved pathologic response in patients with head and neck cancer.
Breakthrough Mechanism Targets Immune Exclusion
Pepinemab, a humanized IgG4 monoclonal antibody, works by blocking Semaphorin 4D (SEMA4D (search)), a potent biological effector that prevents infiltration and activation of immune cells in tumors. By inhibiting SEMA4D's binding to plexin-B1 (search) receptors, pepinemab prevents the collapse of the actin cytoskeleton in dendritic cells, allowing these crucial immune regulators to maintain their homeostatic functions.
The drug's unique approach addresses a critical challenge in cancer immunotherapy: many tumors, particularly HPV-negative head and neck cancers, are considered immunologically "cold" due to exclusion of immune cells from the tumor microenvironment and high levels of immune suppressor cells, making them resistant to immune checkpoint therapy.
Clinical Evidence in Multiple Cancer Types
Data from Vaccinex's collaboration with Emory University's Winship Cancer Center demonstrates pepinemab's ability to facilitate immune cell interactions within highly organized centers of immunity called tertiary lymphoid structures (TLS). Lead investigator Conor Steuer, MD, will present results showing how blocking the SEMA4D (search) inhibitory signal to dendritic cells allows productive, coordinated interactions between SEMA4D+ T cells and dendritic cells within TLS, amplifying mature T cell responses.
In metastatic melanoma patients, neoadjuvant treatment with pepinemab enhanced TLS maturity and correlated with longer recurrence-free survival when combined with immune checkpoint inhibitors. Importantly, the addition of pepinemab to neoadjuvant immune checkpoint treatments did not compound toxicities while enhancing therapeutic benefit.
Addressing Unmet Medical Needs
The clinical significance extends beyond melanoma to head and neck squamous cell carcinoma (HNSCC), where standard of care often involves toxic chemotherapy and radiotherapy in addition to surgery, significantly impacting patients' quality of life. While peri-operative treatment with immunotherapy has shown promising results, many HNSCC tumors remain resistant to checkpoint therapy due to their immunologically cold nature.
Elizabeth Evans, PhD, Senior VP Discovery and Translational Medicine at Vaccinex, emphasized the potential impact: "Pepinemab may represent a solution to this problem, as our data demonstrate the potential of pepinemab to turn immunologically cold tumors, such as HPV-negative and PD-L1-low head and neck cancer, into hot immune centers by inducing robust and mature TLS."
Comprehensive Development Program
Pepinemab is currently being evaluated in multiple clinical trials across various cancer types. The oncology program includes the Phase 1b/2 KEYNOTE-B84 study in combination with KEYTRUDA for recurrent or metastatic head and neck cancer, and a Phase 1b/2 study combining pepinemab with BAVENCIO for metastatic pancreatic adenocarcinoma. Several investigator-sponsored studies are also underway in solid tumors including breast cancer and melanoma.
The drug candidate has demonstrated a favorable safety profile across multiple clinical trials in different cancer and neurological indications, appearing to be well-tolerated without the toxicity concerns that often limit combination immunotherapy approaches.
Scientific Presentations and Future Outlook
The company will present its findings at two major scientific conferences. At the 2025 AACR Annual Meeting in Chicago on April 29, 2025, Evans will present data on pepinemab's mechanism in regulating dendritic cells and its effects in metastatic melanoma patients. The ASCO presentation on June 1, 2025, will focus specifically on the neoadjuvant biomarker trial results in resectable head and neck cancer.
These presentations represent a significant milestone in understanding how TLS formation can be therapeutically induced to enhance immunotherapy effectiveness. The growing excitement around boosting TLS within tumors stems from their demonstrated correlation with clinical benefit and positive response to immune checkpoint therapy, though safe and effective therapies to induce TLS formation have remained elusive until now.