1466 Phase I/II clinical trial of a melanoma vaccine targeting shared nonmutated antigens and a shared mutated neoantigen with an agonistic CD40 antibody (CDX-1140) plus TLR agonist (polyICLC)

<h3>Background</h3> Cancer vaccines have recently shown efficacy in the post-surgical, adjuvant setting, and studies continue to optimize them further, by enhancing selection of relevant antigens and local vaccine adjuvants. We report on a first-in-human approach to treat patients with high-risk melanoma using a vaccine comprised of seven class II MHC-restricted peptides, including six nonmutated melanoma-specific helper peptides (6MHP) and a shared mutated BRAF-V600E neoantigen (neoAg-mBRAF), co-administered locally with a TLR3 agonist (polyICLC) and agonistic CD40 Ab (CDX-1140). We hypothesized that vaccination with CD40 Ab/TLR3 agonist would be safe and would induce strong, durable CD4⁺ T cell responses, and that neoAg-mBRAF would be immunogenic. <h3>Methods</h3> Adult participants with stage II-IV, or ulcerated stage IB, cutaneous or uveal melanoma were enrolled, after definitive treatment, to this open-label, phase I/II study at two centers. All participants received vaccine [6MHP + neoAg-mBRAF + polyICLC] with a dose-escalation allocation of CDX-1140 into the vaccine mixture at one of four dose levels (50, 200, 800, 3000 mcg). Vaccines were administered every 3 weeks x4. Primary endpoints were toxicity (CTCAE v5.0) and immunogenicity (direct IFNγ ELIspot), with a subset also measured by in-vitro stimulated (IVS) IFNγ ELIspot. <h3>Results</h3> Twenty-two eligible participants, clinically free of disease, were enrolled and treated, meeting the enrollment target. Median age was 63.5 years (range 44 – 80) and 9 (41%) were female. Sixteen (73%) were assigned the maximum dose level for CDX-1140. Toxicities were limited to Grade 1 or 2 treatment-related adverse events, with no treatment-related dose-limiting toxicities. CD4⁺ T cell responses to 6MHP in peripheral blood mononuclear cells (PBMC) were found ex vivo in 6 (27%, 95% CI: 11–50%), of which 2 (9%, 95% CI: 1–29%) were persistent to week 25. The T cell response rate was similar (25%) at the highest dose of CDX-1140, with both persistent responses at that dose. T cell responses to neoAg-mBRAF did not meet criteria for positivity on direct IFNγ ELIspot, but one participant had a strong T cell response to neoAg-mBRAF by IVS IFNγ ELIspot (figure 1). <h3>Conclusions</h3> Administration of local CDX-1140 and polyICLC with a melanoma helper peptide vaccine is safe and well-tolerated to 3 mg per dose. The regimen supported immunogenicity of MHC II-restricted melanoma peptides, including the shared neoantigen neoAg-mBRAF. Further optimization of the adjuvant combinations may enhance immune response rates and T cell memory in a next generation phase II trial. <h3>Acknowledgements</h3> We acknowledge the assistance of Donna M Deacon and Marya Dunlap-Brown, and Walter Olson in vialing the neoAg-mBRAF peptide for this trial. <h3>Trial Registration</h3> NCT04364230 (Clinicaltrials.gov). <h3>Ethics Approval</h3> This study involves human participants and was approved by the University of Virginia Institutional Review Board (UVA HSR-IRB # 200006), which served as the central IRB for this multicenter trial. The Cleveland Clinic Institutional Review Board also has a reliance agreement in place. Participants gave informed consent to participate in the study before taking part.