Randomized phase I/II trial adjuvant CD40.HVAC, an immunotherapy engaging dendritic cells (DC), in patients with HPV16+ oropharyngeal carcinoma (OPC).

6018 Background: Up to 70% of OPCs are HPV-mediated predominantly by HPV16. E6/E7 oncoproteins, constitutively expressed in malignant cells, represent optimal immunotherapeutic targets. We evaluated CD40.HVac, a new DC engager combining a humanized IgG4 monoclonal antibody fused to HPV16 E6/E7, designed to target the CD40 receptor on DCs. Methods: This trial enrolled OPC HPV16⁺ patients (pts) in complete remission 16–22weeks (W) post curative treatment. In cohorts 1 (n=11) and 2 (n=11), pts were randomized (5:1) to receive subcutaneously, Hiltonol (1mg) adjuvanted CD40.HVac, 1 and 3 mg, respectively, or placebo, at W0, 4, 24. Dose-limiting toxicity (DLT) was assessed from W0–W6. Blood E6/E7-specific T cells were assessed 2W post-injection using stimulation of PBMCs with vaccine E6/E7 pools of peptides. CD8+T cells were characterized by expression of Activation Induced Markers (AIM). Immune response was defined as a ≥3-fold increase in HPV specific T cell responses over unstimulated controls after in vitro restimulation, or a net increase of ≥ 0.03% reaching at least 0.05% AIM⁺ T cells compared to baseline. Results: Median age was 58 years (IQR 51; 65), 68% were male, 68% were stage I or II, 32% stage III. At entry, 21 pts were lymphopenic (3 grade 3). All pts received the 3 planned injections. Four pts were randomized to placebo, 18 to CD40.HVac. No DLTs nor grade 3-5 adverse events (AEs) were reported. From W0 to W32, all pts treated with CD40.HVac experienced at least 1 vaccine related AE; 5 (28%) experienced at least 1 grade 2 AE while the 13 others experienced only grade 1 AEs. At W6, 77% of pts treated with CD40.HVac in the both 1 mg and 3 mg cohorts exhibited a 27-fold and 42-fold increase from baseline, respectively, in CD4⁺ T cells producing IL-2, IFNγ and/or TNF. By W26, responses were observed in 100% of pts treated with CD40.HVac in both cohorts, with 35-fold (1 mg) and 83-fold (3 mg) increases from baseline. AIM assays confirmed the induction of HPV specific CD4⁺ and CD8⁺ T cell responses. HPV specific CD8⁺ T cell responses were detected in 50% and 44% of pts treated with CD40.HVac at W6 in the 1 mg and 3 mg cohorts, respectively, and in 71% and 44% at W26. HPV specific CD8⁺ T cells displayed a polyfunctional cytotoxic phenotype, expressing IFNγ, TNF, granzyme B and CD107a, along with PD-1, consistent with an activated state. Both CD4⁺ and CD8⁺ T cell responses were durable and persisted up to1 year post-prime vaccination. Only minimal or no increases in HPV specific responses were observed in pts treated with placebo. After a median follow-up of 1 year, no pt presented disease relapse. HPVct DNA monitoring will be presented at the meeting. Conclusions: The safety and immunogenicity of CD40.HVac support further clinical development of this strategy in pts with HPV16+ OPC. Clinical trial information: NCT06007092 .