Project 2: Mechanisms of Resistance to Neoantigen Vaccines in PDAC

项目2:PDAC新抗原疫苗耐药机制

基本信息

  • 批准号:
    10708575
  • 负责人:
  • 金额:
    $ 33.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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WILLIAM G HAWKINS其他文献

WILLIAM G HAWKINS的其他文献

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{{ truncateString('WILLIAM G HAWKINS', 18)}}的其他基金

Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10708573
  • 财政年份:
    2023
  • 资助金额:
    $ 33.69万
  • 项目类别:
Preclinical development of the novel inhibitor of apoptosis proteins S2/IAPinh for cancer therapy
用于癌症治疗的新型凋亡蛋白抑制剂 S2/IAPinh 的临床前开发
  • 批准号:
    10568409
  • 财政年份:
    2022
  • 资助金额:
    $ 33.69万
  • 项目类别:
Preclinical Development of ACXT-3102 for the Treatment of Pancreatic Adenocarcinoma (PDAC)
ACXT-3102 治疗胰腺癌 (PDAC) 的临床前开发
  • 批准号:
    10435565
  • 财政年份:
    2019
  • 资助金额:
    $ 33.69万
  • 项目类别:
Preclinical Development of ACXT-3102 for the Treatment of Pancreatic Adenocarcinoma (PDAC)
ACXT-3102 治疗胰腺癌 (PDAC) 的临床前开发
  • 批准号:
    10251498
  • 财政年份:
    2019
  • 资助金额:
    $ 33.69万
  • 项目类别:
Washington University SPORE in Pancreatic Cancer
华盛顿大学 SPORE 在胰腺癌中的应用
  • 批准号:
    9982223
  • 财政年份:
    2016
  • 资助金额:
    $ 33.69万
  • 项目类别:
Washington University SPORE in Pancreatic Cancer
华盛顿大学 SPORE 在胰腺癌中的应用
  • 批准号:
    9146190
  • 财政年份:
    2016
  • 资助金额:
    $ 33.69万
  • 项目类别:
SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER
SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡
  • 批准号:
    8630870
  • 财政年份:
    2012
  • 资助金额:
    $ 33.69万
  • 项目类别:
SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER
SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡
  • 批准号:
    8219912
  • 财政年份:
    2012
  • 资助金额:
    $ 33.69万
  • 项目类别:
SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER
SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡
  • 批准号:
    8463148
  • 财政年份:
    2012
  • 资助金额:
    $ 33.69万
  • 项目类别:
SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER
SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡
  • 批准号:
    8879063
  • 财政年份:
    2012
  • 资助金额:
    $ 33.69万
  • 项目类别:

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辅助化疗预后生物标志物的分子机制分析
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