Project 1: Combining PARP inhibition with radiation to sensitize HR proficient pancreatic cancers to immunotherapy

项目 1：将 PARP 抑制与放射治疗相结合，使 HR 熟练的胰腺癌对免疫治疗敏感

• 批准号: 10554472
• 负责人: Meredith A Morgan
• 金额: $ 22.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554472
• 关键词: Agreement; Biopsy; Blocking Antibodies; Blood; CD8-Positive T-Lymphocytes; Cancer Etiology; Cell Survival; Cells; Cessation of life; Clinical Management; Clinical Research; Clinical Trials; Combined Modality Therapy; DNA; DNA Damage; DNA biosynthesis; Data; Dependence; Dose; Dose Limiting; Event; FDA approved; Fractionation; Generations; Goals; Immune; Immunocompetent; Immunologic Deficiency Syndromes; Immunotherapy; Innate Immune Response; Interferon Type I; Lesion; Localized Disease; Locally Advanced Malignant Neoplasm; Malignant neoplasm of pancreas; Mediating; Methods; Micrometastasis; Molecular; Molecular Target; Natural Immunity; PARP inhibition; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pattern recognition receptor; Phase; Phase I/II Trial; Phenotype; Poly(ADP-ribose) Polymerase Inhibitor; Property; Radiation; Radiation Dose Unit; Radiation Induced DNA Damage; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Randomized; Resistance; Schedule; Site; Stimulator of Interferon Genes; Survival Rate; T-Cell Depletion; Therapeutic; Therapeutic Index; Toxic effect; Translating; Treatment Efficacy; Treatment outcome; Tumor Immunity; Tumor Promotion; United States; adaptive immune response; adaptive immunity; advanced pancreatic cancer; anti-PD-L1; chemotherapy; clinical investigation; design; ds-DNA; fractionated radiation; gastrointestinal; homologous recombination; immune checkpoint blockade; immunogenicity; immunoregulation; improved; inhibitor; innate immune mechanisms; micronucleus; neoplastic cell; novel; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; phase II trial; pre-clinical; preclinical study; programmed cell death ligand 1; replication stress; response; subcutaneous; synergism; time use; tumor; tumor DNA; tumor growth; tumor microenvironment

PROJECT SUMMARY/ABSTRACT (PROJECT 1) We discovered that inhibitors of the DDR (DNA damage response) enhance radiation-induced T1IFN (Type I interferon)-mediated innate immunity and, subsequently, adaptive immunity. We have also shown that PARP inhibitors are radiation sensitizers with unique properties in inducing lesions at radiation-induced DNA damage sites. In this application, we investigate their combination with radiation as a strategy to induce innate immunity and sensitize PDAC (pancreatic ductal adenocarcinoma) to immunotherapy. We confirm, in agreement with a clinical study, that radiation alone is a weak immune stimulator. In contrast, the combination of radiation with the PARP inhibitor olaparib strongly induces T1IFN-mediated innate immunity in PDAC resulting in sensitization of both local and systemic tumors to immunotherapy. Taken together these data support our proposed clinical trial combining olaparib, radiation and durvalumab in patients with LAPC (locally advanced pancreatic cancer). The overall goal of this proposal is to preclinically develop a strategy combining PARP inhibitors with radiation for sensitizing PDAC to ICB (immune checkpoint blockade) by promoting tumor cell DNA damage and immunogenicity that will be translated to a clinical trial in LAPC patients. We will accomplish this in 3 specific aims. Specific Aim 1 will elucidate novel mechanisms of innate immune modulation and their T1IFN-dependent phenotypic consequences by PARP inhibitors with radiation in PDAC cells. Our preliminary data show, in contrast to PARP inhibitor alone, that the PARP inhibitor olaparib synergizes with radiation to reduce survival and induce a T1IFN innate immune response in HR (homologous recombination) proficient PDAC. Aim 1 will define novel mechanisms of T1IFN generation and its subsequent phenotypic consequences. We anticipate defining novel pattern recognition receptor (PRR) pathways initiated by olaparib and radiation-induced DNA damage or replication stress that result in increased tumor innate immunity. Specific Aim 2 will determine the therapeutic benefit and molecular endpoints of combined therapy with PARP inhibitor, radiation and ICB in PDAC. We will define the local and systemic anti-tumor efficacy and toxicity of high or lower dose per fraction radiation (i.e., SBRT, stereotactic body radiation or standard fractioned radiation) and the optimal schedule with olaparib and anti-PD-L1. We will establish endpoints in tumors and blood reflecting DNA damage, tumor innate and adaptive immunity, as well as the broader immune profile (CyTOF). We expect to achieve a favorable therapeutic index with SBRT that is associated with tumor DNA damage and T1IFN-mediated innate and adaptive immunity. In Specific Aim 3, we will conduct a clinical trial of olaparib, radiation, and durvalumab in patients with LAPC. We will dose escalate olaparib using the Time-to-Event Continual Reassessment Method (TiTE-CRM) with the combination of SBRT (unless otherwise informed by Aim 2) and the PD-L1 blocking antibody durvalumab in patients with LAPC. We anticipate that we will achieve a safe and efficacious combination of olaparib with radiation and durvalumab that promotes maximal immunogenicity and motivates a randomized phase 2 trial to ultimately improve survival in patients with LAPC.

项目摘要/摘要（项目1）