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.

胰腺癌中的HIFU免疫疗法最重要的是，我们发现超声，TLR7/8激动剂与ACD40和检查点的组合抑制（基于新兴人类研究方案建立）有效消除了植入的多站点侵入性 KPC鼠胰腺肿瘤。最近的研究为激动剂的实用性提供了令人信服的证据多组分方案中的CD40（ACD40）抗体治疗胰腺癌，并研究结合带有检查点调节剂和化学疗法的ACD40显示了极大的令人鼓舞的数据。 CD40表示在胰腺癌细胞和绝大多数周围淋巴细胞的子集中。对于PDAC， ACD40单克隆抗体还促进基质降解，树突状细胞成熟和变化巨噬细胞表型，因此是一种免疫疗法的有吸引力的方法。而NCT03214250 （将吉西他滨和阿布沙烷与ACD40和APD-1免疫疗法相结合）产生了非常有希望的结果其中所有接受所有成分的患者均显示转移性胰腺癌的消退未观察到激活，也未治愈患者。可靠地在人类中提供这些治疗胰腺癌由于致密的基质和有限的血管供应而具有挑战性。 MR的初步研究计划于2020年初开始进行指导的超声（MRGFU）烧毁人胰腺肿瘤在斯坦福大学。在这里，我们将将MRGFU与ACD40+检查点抑制剂策略相结合。我们将立即如果结果有前途，则努力转化这种策略。此外，最近的工作还表明了像受体（TLR）一样，7/8激动剂具有治疗效用，特别是在胰腺癌中。 TLR7/8激动剂是由于受体分布在DC的子集上，因此需要翻译。我们的初步数据证明了 TLR7/8和ACD40之间的协同作用，我们建立在AIM中TLR7/8激动剂和ACD40的组合基础上 2。虽然TLR7/8激动剂可以在皮内传递，但直接递送TLR激动剂到肿瘤会产生原位疫苗接种，通过将活化的免疫细胞暴露于癌症抗原中来促进功效。我们的初步数据表明，使用2种处理（静脉注射TLR7/8和CP4），直接治疗的100％消除了肿瘤和60％的遥远KPC肿瘤。人类研究的主要挑战是交付足够数量的TLR7/8激动剂和胰腺癌的抗体，而无需限制剂量的毒性。我们已经制定了一种对温度敏感的脂质体（TSL）策略，以确保足够的TLR7/8提供胰腺癌的激动剂并将其添加到目标2中。通过这样的策略，可以提供8％或更多的策略注射剂量对人肿瘤（至少比游离药物高20倍），并限制了全身毒性。总之，在AIM 1中，我们将将MRGFUS融合到临床上与ACD40+检查点疗法中。之内 AIM 2，我们将进一步将TLR7/8激动剂添加到ACD40协议中。作为翻译的额外一步，我们将分析原代人类胰腺癌细胞，以对TLR7/8和ACD40的影响对增殖。