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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：
Katherine W Ferrara
金额：
$ 61.71万
依托单位：
STANFORD UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10425306
关键词：
Ablation Abraxane Address Agonist Animals Antibodies Antibody Therapy Biological Assay Cell Maturation Cell model Cells Characteristics Clinical Research Combination immunotherapy Data Dendritic Cells Distant Dose Dose-Limiting Ensure Flow Cytometry Focused Ultrasound Focused Ultrasound Therapy Future Head and Neck Cancer Human Hyperthermia Immune Immune checkpoint inhibitor Immune response Immunotherapy Implant KPC model Liposomes Lymphocyte Lymphoma Magnetic Resonance Malignant Neoplasms Malignant neoplasm of pancreas Methods Molecular Monitor Monoclonal Antibodies Mus Myeloid-derived suppressor cells Pancreas Pancreatic Ductal Adenocarcinoma Patients Penetration Pharmaceutical Preparations Phenotype Positron-Emission Tomography Protocols documentation Regulatory T-Lymphocyte Safety Schedule Site T-Cell Activation T-cell inflamed TLR7 gene TNFRSF5 gene Temperature Testing Therapeutic Toll-like receptors Toxic effect Translating Translations Treatment Protocols Tumor Antigens Tumor Volume Vascular blood supply Work anti-CTLA4 anti-PD-1 base checkpoint inhibition checkpoint therapy chemotherapy clinically relevant cohort gastrointestinal gemcitabine imaging modality imaging probe improved in situ vaccination intravenous injection macrophage malignant breast neoplasm mouse model neoplastic cell pancreatic cancer cells pancreatic cancer model pancreatic neoplasm patient derived xenograft model porcine model receptor resiquimod response single cell analysis synergism systemic toxicity transcriptome sequencing tumor ultrasound ultrasound ablation

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.

胰腺癌的HIFU免疫治疗最重要的是，我们发现超声，TLR 7/8激动剂与aCD 40和检查点的组合，抑制（建立在新兴人类研究的方案上）有效地消除了植入的多部位侵入性 KPC小鼠胰腺肿瘤。最近的研究为激动剂的效用提供了令人信服的证据 CD 40（aCD 40）抗体在多组分方案中治疗胰腺癌，以及联合研究 aCD 40与检查点调节剂和化疗显示出非常令人鼓舞的数据。CD 40表达对胰腺癌细胞和绝大多数肿瘤周围淋巴细胞的影响。对于PDAC， aCD 40单克隆抗体还促进基质降解、树突状细胞成熟和改变巨噬细胞表型，因此是一种有吸引力的免疫治疗方法。而NCT 03214250 （将吉西他滨和Abraxane与aCD 40和aPD-1免疫疗法组合）产生了非常有希望的结果其中接受所有组分的所有患者均显示转移性胰腺癌消退，T细胞未观察到活化，患者未治愈。在人类中可靠地提供这些治疗由于致密的间质和有限的血管供应，胰腺癌具有挑战性。MR的初步研究用于消融人类胰腺肿瘤的引导聚焦超声（MRgFUS）计划于2020年初开始在斯坦福大学。在这里，我们将联合收割机MRgFUS与aCD 40+检查点抑制剂策略相结合。我们会立即如果结果有希望，则努力将这种战略转化为现实。此外，最近的研究也表明，类受体（TLR）7/8激动剂具有治疗效用，特别是在胰腺癌中。TLR 7/8激动剂是由于受体在DC亚群上的分布，其是翻译所需的。我们的初步数据显示我们研究了TLR 7/8和aCD 40之间的协同作用，并在Aim中建立了TLR 7/8激动剂和aCD 40的组合。 2.虽然TLR 7/8激动剂可以皮内递送，但是TLR激动剂向肿瘤的直接递送产生了免疫抑制剂。原位接种，通过将活化的免疫细胞暴露于癌抗原来促进功效。我们的初步数据表明，用2次治疗（静脉注射TLR 7/8和CP 4）高达100%的直接治疗肿瘤和60%的远处KPC肿瘤被消除。人类研究的一个主要挑战是足够量的TLR 7/8激动剂和胰腺癌抗体，而没有剂量限制性毒性。我们已经开发了一种温度敏感的脂质体（TSL）策略，以确保足够的TLR 7/8递送胰腺癌的激动剂，并将其添加到目标2。通过这种战略，可以实现8%或更多的注射剂量（至少是游离药物的20倍）并限制全身毒性。总的来说，在目标1中，我们将把MRgFUS消融纳入临床相关的aCD 40+检查点治疗中。内目的2，我们将进一步将TLR 7/8激动剂添加到aCD 40方案。作为翻译的另一步，我们将测定原代人胰腺癌细胞中TLR 7/8和aCD 40对增殖的影响。