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

摘要 我们在肿瘤新抗原的免疫生物学方面做出了重要贡献，并开发了一种 健壮的，公共可用的，经常下载的新抗原预测软件工具套件。使用 在我们之前胰腺癌和SU2C孢子的支持下，我们现在已经完成了两个 PDAC检测新抗原DNA疫苗(NCT03122106)和合成长肽的第一阶段临床试验 (SLP)疫苗(NCT03956056)。初步分析证实，两种新抗原疫苗平台都可以 诱导强大的免疫反应，并表明接受新抗原疫苗治疗的PDAC患者 比预期的临床结果要好。我们最近开发了用于确定II类的优先级的算法 新抗原，并证明了同时包含I类和II类新抗原的优化疫苗改善了 新抗原疫苗的成功。在Leidos Biomedical Research的资助下，我们目前正在测试 在PDAC患者中使用窗口试验设计优化新抗原SLP疫苗(NCT05111353)。 目的1：检验优化的新抗原疫苗可以增加和改善疫苗数量的假设 新抗原特异性T细胞在PDAC中的作用我们目前正在测试优化的新抗原 PDAC患者术前窗口新辅助化疗后的疫苗接种 (NCT05111353)。Window临床试验设计为研究新抗原特异性T细胞提供了机会 接种后肿瘤微环境(TME)的反应。在目标1中，我们将使用来自 严格评估存在于TME中的新抗原特异性T细胞功能生物学的试验 单细胞RNA测序(scRNA-seq)和TCR测序。 目的2：测试创新策略以解决PDAC中cDC1的匮乏问题。我们已经使重要的 对了解cDc1的发育和生物学的贡献。我们最近证明了cDc1 在癌症中协调CD4和CD8免疫反应，以及PDAC损害cDC1的发育， 抑制抗肿瘤免疫。我们目前正在测试一项创新战略，以在 PDAC(NCT04536077)。我们将测试创新策略，以加强PDAC的新抗原疫苗治疗 在体内扩增和许可cDc1。我们还将测试来自NCT05111353和NCT04536077的生物检疫菌 目的：评价cDc1缺失对新抗原疫苗免疫应答的影响。 目的3：验证TIGIT途径抑制对优化的新抗原的反应的假设 PDAC中的疫苗。我们和其他人利用人体样本和临床前模型生成了数据 提示TIGIT途径抑制了PDAC的抗肿瘤免疫反应。我们提出了相关的 研究确定TIGIT信号是否也抑制人PDAC中新抗原特异性T细胞反应。 鉴于抗TIGIT和抗PD-1抗体是 目前正在进行早期临床试验