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: 10697921
• 负责人: Matthew Stephen Block
• 金额: $ 40万
• 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: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697921
• 关键词: Adjuvant; Alleles; Antibodies; Antigens; BRAF gene; Benchmarking; Binding; Biocompatible Materials; Biological Assay; CD8-Positive T-Lymphocytes; CTAG1 gene; CTLA4 gene; Cancer Patient; Clinical; Clinical Oncology; Combined Vaccines; Cytotoxic T-Lymphocytes; Data; Development; Differentiation Antigens; Disease; Engineering; Formulation; Glutamic Acid; Goals; HLA-A2 Antigen; Human; Immune checkpoint inhibitor; Immunity; Interferon Type II; Kinetics; Ligands; Liquid substance; MHC Class I Genes; Measures; Melanoma Cell; Melanoma Vaccine; Metastatic Melanoma; Modeling; Monophenol Monooxygenase; Mus; Mutate; Normal tissue morphology; Outcome; Ovalbumin; Patients; Peptides; Pharmacology and Toxicology; Phase; Polymers; Positioning Attribute; Privatization; Production; Program Development; Property; Proteins; Published Comment; Recurrence; Refractory; Research Personnel; Resected; Resistance; SILV gene; Safety; Small Business Technology Transfer Research; System; T cell response; T-Lymphocyte; TLR7 gene; Techniques; Therapeutic; Transgenic Mice; Tumor Burden; Tumor Suppression; Vaccinated; Vaccine Adjuvant; Vaccines; Validation; Valine; Writing; anti-PD-1; anti-PD1 antibodies; antigen-specific T cells; assay development; cancer/testis antigen; checkpoint inhibition; checkpoint therapy; clinical translation; controlled release; experience; high risk; human subject; immune checkpoint; immunogenic; immunogenicity; improved; in silico; melanoma; method development; mouse model; mutant; neoantigen vaccine; neoantigens; next generation sequencing; novel; pre-clinical; product development; programmed cell death protein 1; prophylactic; resiquimod; response; targeted treatment; therapeutic vaccine; tumor; vaccine efficacy

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 尽管免疫检查点抑制剂和靶向免疫检查点抑制剂可以显著改善结果， 在这些治疗中，大多数转移性BRAF突变黑色素瘤患者最终会经历其 疾病对免疫检查点抑制剂耐药的一个关键原因是缺乏黑色素瘤特异性T细胞， 细胞，但不幸的是，大多数早期黑色素瘤疫苗旨在扩增黑色素瘤特异性T细胞， 未能证明其益处。下一代测序和计算机肽-HLA结合预测 研究人员可以给癌症患者接种新抗原疫苗，这些新抗原是一种不表达的肽， 但只在肿瘤中发现。虽然新抗原疫苗有很大的希望，但关键是 局限性在于新抗原通常是私有的，因此不可能制造“现成的” 新抗原疫苗，将适用于一大群患者。我们和其他人发现， 黑色素瘤患者可以对突变的BRAF（缬氨酸到谷氨酸， 位置600）。我们已经进一步证明，HLA-A2结合突变BRAF肽（mBRAFp）是一种与HLA-A2结合的突变BRAF肽。 在HLA-A2转基因小鼠中具有高度免疫原性。在这里，我们提出， V600 E突变的BRAF在HLA-A2的背景下具有扩增黑素瘤特异性T细胞的潜力。作为 共享的新抗原，mBRAFp是约20-25%的黑素瘤患者（40- 50%）的相关肿瘤靶标。 50%的黑色素瘤患者携带BRAF V600 E x 50%的患者携带HLA-A2）。这个现成的 治疗性疫苗可作为单一疗法用于患有高风险切除的黑色素瘤或患有高风险切除的黑色素瘤的患者。 最小肿瘤负荷。它也可以与抗PD-1联合用于难治性黑色素瘤患者。 免疫检查点抑制剂疗法和靶向疗法。我们的疫苗由mBRAFp和瑞喹莫特组成 (RSQ)作为佐剂配制在CAPRO™ -一类新的专有生物可降解液体聚合物， 提供抗原和佐剂的局部控制释放。之前我们发现（1）小鼠 用CAPRO负载的卵清蛋白（OVA）和RSQ免疫小鼠， 和CD 8 T细胞应答，和（2）CAPRO负载的mBRAF 0和RSQ引发抗原特异性T细胞应答 在HLA-A2转基因小鼠中。基于这些有希望的结果，我们已经启动了临床前产品 开发计划涉及疫苗成分的CMC和制剂开发， 收到FDA对我们的IND前询问的书面意见。该项目的目标是 定义疫苗产品，并为IND的全面CMC和药理学/毒理学研究奠定基础 应用程序.为了实现这一目标，我们将首先评估预防性和治疗性抗肿瘤功效 我们的疫苗产品在表达mBRAFp的HLA-A2转基因小鼠模型中的安全性， 与使用Montanide（一种临床使用的疫苗佐剂系统）的制剂进行比较。我们还将 探索疫苗与免疫检查点抑制（抗PD 1）相结合的潜力。然后我们将开发 疫苗成分和最终疫苗产品的分析测定，并生成IND支持数据，以满足 FDA的CMC要求。