Phase I/II clinical trial of a melanoma vaccine targeting shared non-mutated antigens and a shared mutated BRAF neoantigen with an agonistic CD40 antibody (CDX-1140) plus TLR3 agonist (poly-ICLC)

  • J Immunother Cancer. 2026 Mar 3;14(3):e013613. doi: 10.1136/jitc-2025-013613.
Emily K Ninmer  1 ,  Gina R Petroni  2 ,  Brian R Gastman  3  4 ,  Elizabeth M Gaughan  5 ,  James M Isaacs  6 ,  Kathleen Haden  1 ,  Varinder Kaur  5 ,  Nolan A Wages  2  7 ,  Kimberly A Chianese-Bullock  1  8 ,  Kelly T Smith  1  8 ,  Paul Wright  1 ,  Jennifer Bryant  1 ,  Marya Dunlap-Brown  1  8 ,  Jack A Engel  1  9 ,  Stefan Bekiranov  8  10 ,  Ileana S Mauldin  1  8 ,  Thach-Giao Truong  6 ,  Timothy N J Bullock  11 ,  Craig L Slingluff Jr  12  8
Affiliations
  • 1. Department of Surgery/Division of Surgical Oncology, University of Virginia Health System, Charlottesville, Virginia, USA.
  • 2. Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • 3. Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA.
  • 4. Iovance Biotherapeutics Inc, San Carlos, California, USA.
  • 5. Department of Medicine/Division of Hematology/Oncology, University of Virginia Health System, Charlottesville, Virginia, USA.
  • 6. Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  • 7. Present Affiliation: Department of Biostatistics, School of Public Health, Virginia Commonwealth University, Richmond, Virginia, USA.
  • 8. Cancer Center, University of Virginia Health System, Charlottesville, Virginia, USA.
  • 9. Present Affiliation: Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • 10. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
  • 11. Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • 12. Department of Surgery/Division of Surgical Oncology, University of Virginia Health System, Charlottesville, Virginia, USA [email protected].
PMID: 41775435 DOI: 10.1136/jitc-2025-013613
Abstract

Background: For patients with high-risk melanoma who are unresponsive or intolerant to immune checkpoint inhibitors, Cancer vaccines may provide benefit with a favorable toxicity profile. CD4+ T cells provide essential help to dendritic cells (DCs) for optimal CD8+ T cell priming in the antitumor response, and induction of tumor-cognate CD4+ T cell responses may enhance vaccine efficacy. We report on a first-in-human approach to treat patients with high-risk melanoma using a vaccine composed of six non-mutated melanoma-specific helper peptides (6MHP) and a shared mutated BRAF-V600E neoantigen helper peptide (mBRAF) co-administered locally with a TLR3 Agonist (poly-ICLC) and agonistic CD40 antibody (CDX-1140).

Methods: Adults with high-risk melanoma arising from cutaneous, mucosal, or ocular primary sites who were rendered clinically free of disease after definitive treatment were enrolled to this nonrandomized phase I/II trial (NCT04364230) designed to assess safety and immunogenicity. Participants received vaccine (6MHP+mBRAF+poly-ICLC) with a dose-escalation allocation of CDX-1140 into the vaccine mixture at one of four dose levels (50, 200, 800, 3000 μg). Vaccines were administered at 3-week intervals for four doses. Primary endpoints were safety and peripheral CD4+ T cell response. Exploratory analysis to characterize the vaccine site microenvironment was performed.

Results: Of 22 eligible participants, 11 (50%) had ocular melanoma. Sixteen (73%) received the maximum CDX-1140 dose. Toxicities were limited to grade 1 or 2 treatment-related adverse events, with no dose-limiting toxicities reported. Peripheral CD4+ T cell responses to 6MHP were found ex vivo in six (27%, 95% CI 11% to 50%), including four with the maximum CDX-1140 dose. One had a durable and persistent T cell response to week 25. T cell responses to mBRAF did not meet criteria for positivity ex vivo, but one participant had a durable response after in vitro stimulation, with expansion of multifunctional Th1-polarized CD4+ T cells. Favorable immune-related changes were observed at the vaccine site, including CDX-1140-mediated increases in mature (DC-LAMP+) DCs.

Conclusions: The vaccine was safe, well-tolerated, and immunogenic. Optimization of vaccines that include agonistic CD40 antibody is needed to enhance immunogenicity. Induction of a multifunctional CD4+ T cell response to mBRAF supports targeting shared mutated neoantigens with melanoma vaccines.

Trial registration number: NCT04364230.

Keywords
Immunotherapy; Vaccine; co-stimulatory molecules.
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