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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.

hifu免疫治疗胰腺癌