Project 2: Mechanisms of Resistance to Neoantigen Vaccines in PDAC

项目2：PDAC新抗原疫苗耐药机制

• 批准号: 10708575
• 负责人: WILLIAM G HAWKINS
• 金额: $ 33.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-28 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708575
• 关键词: Address; Adjuvant Chemotherapy; Agonist; Algorithms; Biology; Biomedical Research; CD8B1 gene; Clinical Trials; Clinical Trials Design; Correlative Study; Coupled; DNA Vaccines; Data; Development; Dimensions; Enrollment; FLT3 ligand; Functional disorder; Funding; Generations; Human; Immune response; Impairment; Licensing; Malignant Neoplasms; Malignant neoplasm of pancreas; Neoadjuvant Therapy; Operative Surgical Procedures; Pathway interactions; Patients; Peptide Vaccines; Phase I Clinical Trials; Pre-Clinical Model; Publishing; Resistance; Role; Signal Transduction; Software Tools; Specimen; Synthetic Antigens; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Tumor Immunity; Tumor Tissue; Universities; Vaccination; Vaccine Design; Vaccine Therapy; Vaccines; Washington; anti-PD1 antibodies; anti-tumor immune response; antigen-specific T cells; cancer immunobiology; cancer immunotherapy; early phase clinical trial; exhaustion; functional improvement; functional status; improved; in vivo; innovation; manufacture; neoantigen vaccine; neoantigens; pancreatic ductal adenocarcinoma model; patient population; peripheral blood; pre-clinical; predict clinical outcome; resistance mechanism; response; restraint; safety assessment; single-cell RNA sequencing; success; translational study; trial design; tumor; tumor microenvironment; vaccine platform

ABSTRACT We have made important contributions to the immunobiology of cancer neoantigens, and have developed a robust, publically available, and frequently downloaded suite of software tools for neoantigen prediction. With support from our previous SPORE in Pancreatic Cancer and SU2C, we have now completed enrollment to two phase 1 clinical trials in PDAC testing neoantigen DNA vaccines (NCT03122106) and synthetic long peptide (SLP) vaccines (NCT03956056). Preliminary analyses confirm that both neoantigen vaccine platforms can induce robust immune responses, and suggest that PDAC patients treated with neoantigen vaccines have better than predicted clinical outcomes. We recently developed algorithms for the prioritization of class II neoantigens and demonstrated that optimized vaccines incorporating both class I and II neoantigens improve the success of neoantigen vaccines. With funding from Leidos Biomedical Research, we are currently testing optimized neoantigen SLP vaccines in PDAC patients using a window trial design (NCT05111353). Aim 1: Test the hypothesis that optimized neoantigen vaccines can increase the number and improve the function of neoantigen-specific T cells in PDAC. We are currently testing optimized neoantigen vaccines in PDAC patients following neoadjuvant chemotherapy in the window prior to surgery (NCT05111353). The window clinical trial design provides the opportunity to study neoantigen-specific T cell responses in the tumor microenvironment (TME) after vaccination. In Aim 1, we will use biospecimens from the trial to rigorously assess the functional biology of neoantigen-specific T cells present in the TME using coupled single-cell RNA sequencing (scRNA-seq) and TCR sequencing. Aim 2: Test innovative strategies to address the paucity of cDC1 in PDAC. We have made important contributions to understanding the development and biology of cDC1. We recently demonstrated that cDC1 orchestrate CD4 and CD8 immune responses in cancer, and that PDAC impairs development of cDC1, restraining antitumor immunity. We are currently testing an innovative strategy to expand and license cDC1 in PDAC (NCT04536077). We will test innovative strategies to enhance neoantigen vaccine therapy in PDAC by expanding and licensing cDC1 in vivo. We will also test biospecimens from NCT05111353 and NCT04536077 to evaluate the impact of cDC1 paucity on the response to neoantigen vaccines. Aim 3: Test the hypothesis that the TIGIT pathway restrains the response to optimized neoantigen vaccines in PDAC. We and others have generated data using human specimens and preclinical models suggesting that the TIGIT pathway restrains antitumor immune responses in PDAC. We propose correlative studies to determine if TIGIT signaling also restrains neoantigen-specific T cell responses in human PDAC. These studies have immediate translational relevance given that anti-TIGIT and anti-PD-1 antibodies are currently being tested in early phase clinical trials

抽象的 我们已经为癌症新抗原的免疫生物学做出了重要贡献，并开发了 强大的，公开可用的，并且经常下载的软件工具套件，用于新抗原预测。和 我们以前在胰腺癌和SU2C的孢子的支持，我们现在已经完成了两个 PDAC测试新抗原DNA疫苗（NCT03122106）和合成长肽的临床试验。 （SLP）疫苗（NCT03956056）。初步分析证实，两个新抗原疫苗平台都可以 诱导强大的免疫反应，并建议用新抗原疫苗治疗的PDAC患者具有 比预测的临床结果更好。我们最近开发了II类优先级的算法 Neoantigens并证明了融合了I类和II新抗原的优化疫苗改善了 新抗原疫苗的成功。在Leidos生物医学研究的资助下，我们目前正在测试 使用窗户试验设计（NCT05111353），在PDAC患者中优化了新抗原SLP疫苗。 目标1：检验假设，即优化的新抗原疫苗可以增加数量并改善 新抗原特异性T细胞在PDAC中的功能。我们目前正在测试优化的新抗原 新辅助化疗后，PDAC患者的疫苗在手术前的窗户中 （NCT05111353）。窗口临床试验设计提供了研究新抗原特异性T细胞的机会 疫苗接种后肿瘤微环境（TME）的反应。在AIM 1中，我们将使用来自 试验严格评估TME中存在的新抗原特异性T细胞的功能生物学 单细胞RNA测序（SCRNA-SEQ）和TCR测序。 目标2：测试创新策略，以解决PDAC中CDC1的稀少。我们很重要 了解CDC1的发展和生物学的贡献。我们最近证明了CDC1 在癌症中编排CD4和CD8免疫反应，并且PDAC会损害CDC1的发展， 限制抗肿瘤免疫力。我们目前正在测试一种创新策略，以扩展和许可CDC1 PDAC（NCT04536077）。我们将测试创新策略，以增强PDAC中的新抗原疫苗疗法 在体内扩展和许可Cdc1。我们还将从NCT05111353和NCT04536077测试生物测量 评估CDC1贫困对新抗原疫苗反应的影响。 AIM 3：检验Tigit途径限制对优化新抗原的反应的假设 PDAC中的疫苗。我们和其他人使用人类标本和临床前模型生成了数据 提示TIGIT途径限制了PDAC中的抗肿瘤免疫反应。我们提出相关性 研究确定TIGIT信号是否还限制了人类PDAC中新抗原特异性T细胞反应。 鉴于抗试剂和抗PD-1抗体是 目前正在早期临床试验中进行测试