Project Details
Description
Abstract
Despite the dramatic improvement in outcomes afforded by immune checkpoint inhibitors and targeted therapies,
most patients with metastatic BRAF-mutated melanoma ultimately experience progression of their disease. One
key reason for resistance to immune checkpoint inhibitors is a paucity of melanoma-specific T cells, but
unfortunately, the majority of early melanoma vaccines meant to expand melanoma-specific T cells have failed
to demonstrate benefit. Next generation sequencing and in silico peptide-HLA binding prediction have allowed
investigators to vaccinate cancer patients against neoantigens – peptides that are not expressed by any normal
tissues but are only found in tumors. Although neoantigen vaccines hold great promise, a key limitation 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 that melanoma patients can
mount an endogenous T cell response to a mutated BRAF (valine to glutamic acid at position 600). We have
further demonstrated that an HLA-A2-binding mutated BRAF peptide (mBRAFp) is highly immunogenic in HLA-
A2-transgenic mice. Here we propose that an immunogenic vaccine targeting V600E-mutated BRAF in the
context of HLA-A2 has the potential to expand melanoma-specific T cells. As a shared 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-shelf therapeutic vaccine may be used
as a monotherapy for patients with high-risk resected melanoma or with minimal tumor burden. It may also be
combined with anti-PD-1 for patients with melanoma that is refractory to immune 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) mice vaccinated with ovalbumin (OVA) and RSQ loaded
in CAPRO developed long-lasting OVA-specific antibody and CD8 T cell responses, and (2) CAPRO-loaded
mBRAFp and RSQ elicited antigen-specific T cell response in HLA-A2 transgenic mice. Based on these
promising results, we have initiated preclinical product development program involving CMC of the vaccine
ingredients and formulation development and have received written comments from the FDA in response to our
pre-IND inquiry. The goal of this project is to define the vaccine product and set the stage for full CMC and
pharmacology/toxicology studies toward an IND application. To accomplish this goal, we will first evaluate the
prophylactic and therapeutic antitumor efficacy and safety of our vaccine product in a mBRAFp-expressing HLA-
A2 transgenic mouse model with direct comparison with a formulation using Montanide (a clinically used vaccine
adjuvant system). We will also explore the potential of combining vaccine with immune checkpoint inhibition
(anti-PD1). We will then develop analytical assays for vaccine ingredients and final vaccine product, and
generate IND-enabling data to meet CMC requirements of the FDA.
Status | Finished |
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Effective start/end date | 3/1/23 → 2/29/24 |
Funding
- National Cancer Institute: $147,823.00
- National Cancer Institute: $399,979.00
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