Despite the dramatic improvement in outcomes afforded by immune checkpoint inhibitors and targetedtherapies, most patients with metastatic BRAF-mutated melanoma ultimately experience progression of theirdisease. One key reason for resistance to immune checkpoint inhibitors is a paucity of melanoma-specific Tcells, but unfortunately, the majority of early melanoma vaccines meant to expand melanoma-specific T cellshave failed to demonstrate benefit. Next generation sequencing and in silico peptide-HLA binding predictionhave allowed investigators to vaccinate cancer patients against neoantigens - peptides that are not expressedby any normal tissues but are only found in tumors. Although neoantigen vaccines hold great promise, a keylimitation is the fact that neoantigens are generally private, thus it is not possible to make an "off-the-shelf"neoantigen vaccine that will be appropriate for a large group of patients. We and others have found thatmelanoma patients can mount an endogenous T cell response to a mutated BRAF (valine to glutamic acid atposition 600). We have further demonstrated that an HLA-A2-binding mutated BRAF peptide (mBRAFp) ishighly immunogenic in HLA-A2-transgenic mice. Here we propose that an immunogenic vaccine targetingV600E-mutated BRAF in the context of HLA-A2 has the potential to expand melanoma-specific T cells. As ashared neoantigen, mBRAFp is a relevant tumor target for approximately 20-25% of melanoma patients (40-50% of melanoma patients harboring BRAF V600E x 50% of patients harboring HLA-A2). This off-the-shelftherapeutic vaccine may be used as a monotherapy for patients with high-risk resected melanoma or withminimal tumor burden. It may also be combined with anti-PD-1 for patients with melanoma that is refractory toimmune checkpoint inhibitor therapy and targeted therapy. Our vaccine consists of mBRAFp and resiquimod(RSQ) as adjuvant formulated in CAPRO⢠- a new class of proprietary biodegradable liquid polymers,providing local controlled release of both the antigen and adjuvant. Previously we found that (1) micevaccinated with ovalbumin (OVA) and RSQ loaded in CAPRO developed long-lasting OVA-specific antibodyand CD8 T cell responses, and (2) CAPRO-loaded mBRAFp and RSQ elicited antigen-specific T cell responsein HLA-A2 transgenic mice. Based on these promising results, we have initiated preclinical productdevelopment program involving CMC of the vaccine ingredients and formulation development and havereceived written comments from the FDA in response to our pre-IND inquiry. The goal of this project is todefine the vaccine product and set the stage for full CMC and pharmacology/toxicology studies toward an INDapplication. To accomplish this goal, we will first evaluate the prophylactic and therapeutic antitumor efficacyand safety of our vaccine product in a mBRAFp-expressing HLA-A2 transgenic mouse model with directcomparison with a formulation using Montanide (a clinically used vaccine adjuvant system). We will alsoexplore the potential of combining vaccine with immune checkpoint inhibition (anti-PD1). We will then developanalytical assays for vaccine ingredients and final vaccine product, and generate IND-enabling data to meetCMC requirements of the FDA.
Public Health Relevance Statement: PROJECT NARRATIVE
Combining a mutant BRAF peptide - the only known shared melanoma neoantigen with a novel biomaterial
platform, this collaborative project between clinical oncology and biomaterial engineering may ultimately lead to
clinical translation of an effective off-the-shelf therapeutic vaccine with significant positive impact on the lives of
20 to 25% of all melanoma patients.
Project Terms: <αPD-1><αPD1> 