Neoadjuvant Pepinemab Primes Tumor Immunity

Pepinemab (pepi), a semaphorin 4D–blocking antibody, has demonstrated the ability to counteract resistance mechanisms such as immune exclusion and myeloid-derived suppression in both preclinical and clinical settings. Researchers conducted a neoadjuvant biomarker–driven study to assess the effects of pepi, alone and in combination with immune checkpoint blockade (ICB), on the immune landscape within tumors and peripheral blood of patients with resectable head and neck squamous cell carcinoma (HNSCC).

The results will be presented at the American Society of Clinical Oncology 2025 Annual Meeting, from May 30 to June 3, 2025.

The primary objective was biomarker analysis, with clinical end points including pathologic major response, safety, surgical delay, recurrence-free survival, and overall survival. Pretreatment and post-treatment (surgically resected) tumor and blood samples were analyzed to assess the spatial organization of tumor and immune cell populations using high dimensional techniques, including multiplex immunohistochemistry with more than 36 markers and 32-color flow cytometry. Biomarker findings were stratified according to demographic variables and clinical outcomes.

The researchers enrolled 34 patients with a median age of 63 years; 82.4% had negative test results for human papilloma virus (HVP)/p16. Patients were randomly assigned to receive a single dose of pepi alone, pepi combined with ipilimumab, pepi combined with nivolumab, ipilimumab alone, or nivolumab alone (n=6 per group) or to a no-treatment control group (n=4). Surgical resection was performed between days 17 and 36 after treatment. All patients underwent surgery without delay. No additional or unexpected treatment-related adverse events (TRAEs) were reported in the pepi combination groups; nine of ten patients who experienced TRAEs had grade 1-2 events.

Biomarker analyses were stratified by HPV status due to substantial differences between the highly infiltrated tumor microenvironment (TME) in HPV-positive tumors and the immunologically cold TME in HPV-negative tumors. Among the 24 resected HPV-negative tumors available for analysis, an increase in intratumoral tertiary lymphoid structures (TLS) was observed in those obtained from cohorts receiving pepi. In contrast, in tumors from cohorts not treated with pepi, B cells were typically restricted to the tumor margins and excluded from the tumor core. Notably, patients treated with the pepi plus nivolumab combination showed a significant increase in mature TLS density, characterized by CD21+ follicular dendritic cells and CD23+ germinal center B cells, compared with those receiving pepi or nivolumab alone and those receiving no treatment.

This was an unexpected finding because mature TLS are typically rare in poorly immunogenic HPV-negative HNSCC. Clinical evaluations of pathologic response and recurrence-free survival are ongoing. “Neoadjuvant treatment with pepi enhanced the density and maturity of TLS deep within the tumor which was most prominent in combination with nivo [nivolumab] notably in HPV-negative disease. Pepi represents a novel strategy to boost tumor immunity and organization of functional TLS to overcome limitations of ICB in HPV- HNSCC,” the researchers concluded.