Neoadjuvant biomarker trial of pepinemab to enhance nivolumab or ipilimumab activity in resectable head and neck cancer.

103 Background: Neoadjuvant treatment with immune checkpoint blockade (ICB) improves clinical benefit in patients with multiple types of cancers. Window of opportunity studies permit integrated assessments of safety and efficacy, including biomarker assessments of treatment effects and mechanisms of resistance in the tumor microenvironment. SEMA4D blocking antibody, pepinemab (pepi), has been reported to overcome resistance mechanisms including immune exclusion and myeloid suppression in preclinical and clinical studies. We conducted a neoadjuvant integrated biomarker study (NCT03690986) to evaluate the effect of pepi alone and in combination with ICB on the immune profile in the tumor and blood of patients with resectable head and neck squamous cell carcinoma (HNSCC). Methods: Patients were randomized to receive one dose of either pepi alone, pepi/ipilimumab (ipi), pepi/nivolumab (nivo), ipi, nivo (n = 6 patients/group), or no treatment (n = 4); followed by surgery within days 17-36. The primary objective is biomarker assessments; clinical endpoints include pathologic response (pMR), safety, surgical delays, RFS, and OS. Analysis of pretreatment and surgically resected tissue and blood to evaluate spatial distribution of tumor and immune populations employed high dimensional 36+ multiplex IHC and 32-color flow cytometry. Biomarker results were stratified by demographic and clinical outcome measures. Results: Thirty-four patients were enrolled (median age 63 (58-69); 70.6% male; 79.4% OC, 20.6% OP; 82.4% HPV/p16 Neg). All patients proceeded to surgery without delay; no additional or unexpected TRAEs were observed in pepi combinations; 9/10 patients who experienced TRAEs were Grade 1-2. Biomarker analysis was stratified by HPV status due to vast difference between highly infiltrated HPV+ compared to immunologically cold HPV- TME. Among 24 available HPV- resected tumors,an increase in the number of intratumoral tertiary lymphoid structures (TLS) was observed in pepinemab containing cohorts, whereas B cells lined the tumor edge and were generally excluded from tumor bed in cohorts lacking pepinemab. A significant increase in density of mature TLS (including CD21+ follicular DC and CD23+ germinal center B cells) was observed in patients treated with pepi+nivo compared with pepi or nivo alone and untreated patients. This finding was unexpected, as mature TLS are generally rare in poorly immunogenic HPV-negative HNSCC. Clinical assessments of pathologic response and RFS are being analyzed. Conclusions: Neoadjuvant treatment with pepi enhanced the density and maturity of TLS deep within the tumor which was most prominent in combination with nivo 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. Clinical trial information: NCT03690986 .