A Novel Melanoma Vaccine Based on a Shared Neoantigen and a Liquid Polymer Platform

基于共享新抗原和液体聚合物平台的新型黑色素瘤疫苗

• 批准号: 10888553
• 负责人: Matthew Stephen Block
• 金额: $ 14.78万
• 依托单位: TREKKA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10888553
• 关键词: Adjuvant; Antibodies; Antigens; BRAF gene; Binding; Biocompatible Materials; Biological Assay; CD8-Positive T-Lymphocytes; Cancer Patient; Clinical; Clinical Oncology; Combined Vaccines; Data; Development; Disease; Engineering; Formulation; Glutamic Acid; Goals; HLA-A2 Antigen; Immune checkpoint inhibitor; Liquid substance; Melanoma Vaccine; Mus; Mutate; Normal tissue morphology; Outcome; Ovalbumin; Patients; Peptides; Pharmacology and Toxicology; Polymers; Positioning Attribute; Privatization; Program Development; Published Comment; Refractory; Research Personnel; Resected; Resistance; Safety; System; T cell response; T-Lymphocyte; Therapeutic; Transgenic Mice; Tumor Burden; Vaccinated; Vaccine Adjuvant; Vaccines; Valine; Writing; anti-PD-1; antigen-specific T cells; checkpoint inhibition; checkpoint therapy; clinical translation; controlled release; experience; high risk; immunogenic; improved; in silico; melanoma; mouse model; mutant; neoantigen vaccine; neoantigens; next generation sequencing; novel; pre-clinical; product development; prophylactic; resiquimod; response; targeted treatment; therapeutic vaccine; tumor

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.

摘要