HIFU-immunotherapy in pancreatic cancer

胰腺癌的 HIFU 免疫治疗

基本信息

  • 批准号:
    10425306
  • 负责人:
  • 金额:
    $ 61.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

HIFU-immunotherapy in pancreatic cancer Most importantly, we find that the combination of ultrasound, TLR7/8 agonists with aCD40 and checkpoint inhibition (building on a protocol in emerging human studies) efficiently eliminated implanted multisite invasive KPC murine pancreatic tumors. Recent studies have provided compelling evidence as to the utility of agonist CD40 (aCD40) antibodies within multicomponent protocols to treat pancreatic cancer, and studies combining aCD40 with checkpoint modulators and chemotherapy have shown highly encouraging data. CD40 is expressed on a subset of pancreatic cancer cells and the overwhelming majority of peritumoral lymphocytes. For PDAC, the aCD40 monoclonal antibody also promotes stromal degradation, dendritic cell maturation and alters macrophage phenotype, and therefore is an attractive approach for immunotherapy. While NCT03214250 (combining gemcitabine and Abraxane with aCD40 and aPD-1 immunotherapy) yielded very promising results in which all patients receiving all components demonstrated regression of metastatic pancreatic cancer, T cell activation was not observed and patients were not cured. Reliably delivering these treatments in human pancreatic cancer is challenging due to the dense stroma and limited vascular supply. Initial studies of MR guided focused ultrasound (MRgFUS) to ablate human pancreatic tumors are scheduled to begin in early 2020 at Stanford. Here, we will combine MRgFUS with an aCD40+checkpoint inhibitor strategy. We will immediately work to translate such a strategy if results are promising. Further, recent work has also demonstrated that toll like receptor (TLR)7/8 agonists have therapeutic utility, particularly in pancreatic cancer. TLR7/8 agonists are desirable for translation due to the distribution of receptors on subsets of DCs. Our preliminary data demonstrate synergy between TLR7/8 and aCD40, and we build on the combination of TLR7/8 agonists and aCD40 in Aim 2. While TLR7/8 agonists can be delivered intradermally, the direct delivery of TLR agonists to tumors yields an in situ vaccination that facilitates efficacy by exposing activated immune cells to cancer antigen. Our preliminary data indicate that with 2 treatments (with intravenous injection of TLR7/8 and CP4) up to 100% of directly-treated tumors and 60% of distant KPC tumors were eliminated. A major challenge for human studies is to deliver sufficient quantities of TLR7/8 agonists and antibodies to pancreatic cancer without dose-limiting toxicity. We have developed a temperature-sensitive liposomal (TSL) strategy to assure adequate delivery of TLR7/8 agonists to pancreatic cancer and add this in Aim 2. With such a strategy, it is feasible to deliver 8% or more of the injected dose to a human tumor (at least 20 fold more than free drug) and limit systemic toxicity. In summary, within Aim 1, we will incorporate MRgFUS ablation into clinically-relevant aCD40+checkpoint therapy. Within Aim 2, we will further add TLR7/8 agonists to an aCD40 protocol. As an additional step toward translation, we will assay primary human pancreatic cancer cells as to the effect of TLR7/8 and aCD40 on proliferation.
hifu免疫治疗胰腺癌

项目成果

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Katherine W Ferrara其他文献

Katherine W Ferrara的其他文献

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{{ truncateString('Katherine W Ferrara', 18)}}的其他基金

Pediatric volumetric ultrasound scanner
儿科体积超声扫描仪
  • 批准号:
    10739411
  • 财政年份:
    2023
  • 资助金额:
    $ 61.71万
  • 项目类别:
High Resolution Ultrasound in Interventional Radiology
介入放射学中的高分辨率超声
  • 批准号:
    10584507
  • 财政年份:
    2022
  • 资助金额:
    $ 61.71万
  • 项目类别:
High Resolution Ultrasound in Interventional Radiology
介入放射学中的高分辨率超声
  • 批准号:
    10448971
  • 财政年份:
    2022
  • 资助金额:
    $ 61.71万
  • 项目类别:
Imaging Modulation of Immune Phenotype
免疫表型的成像调节
  • 批准号:
    10548151
  • 财政年份:
    2021
  • 资助金额:
    $ 61.71万
  • 项目类别:
Imaging Modulation of Immune Phenotype
免疫表型的成像调节
  • 批准号:
    10113064
  • 财政年份:
    2021
  • 资助金额:
    $ 61.71万
  • 项目类别:
Quantitative volumetric ultrasonic and photoacoustic tomography
定量体积超声和光声断层扫描
  • 批准号:
    10374704
  • 财政年份:
    2021
  • 资助金额:
    $ 61.71万
  • 项目类别:
Imaging Modulation of Immune Phenotype
免疫表型的成像调节
  • 批准号:
    10334545
  • 财政年份:
    2021
  • 资助金额:
    $ 61.71万
  • 项目类别:
Quantitative volumetric ultrasonic and photoacoustic tomography
定量体积超声和光声断层扫描
  • 批准号:
    10541211
  • 财政年份:
    2021
  • 资助金额:
    $ 61.71万
  • 项目类别:
HIFU-immunotherapy in pancreatic cancer
胰腺癌的 HIFU 免疫治疗
  • 批准号:
    10654577
  • 财政年份:
    2020
  • 资助金额:
    $ 61.71万
  • 项目类别:
HIFU-immunotherapy in pancreatic cancer
胰腺癌的 HIFU 免疫治疗
  • 批准号:
    10054764
  • 财政年份:
    2020
  • 资助金额:
    $ 61.71万
  • 项目类别:

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通过 FAK 抑制作用的瞬时组织“启动”可损害胰腺癌进展并提高对吉西他滨/Abraxane 的敏感性
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