Project 1: Developing immune checkpoint controlled-release biomaterials for cancer immunotherapy

项目1：开发用于癌症免疫治疗的免疫检查点控释生物材料

• 批准号: 10328036
• 负责人: TODD D GIORGIO
• 金额: $ 5.13万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328036
• 关键词: Abraxane; Academic Medical Centers; Affect; African American; Animals; Antibody Therapy; Biocompatible Materials; Biological; C57BL/6 Mouse; Cancer Center; Cardiotoxicity; Cells; Clinical; Clinical Trials; Death Rate; Disease; Doctor of Philosophy; Dose; Dose-Limiting; Drug Kinetics; Extramural Activities; Flow Cytometry; Formulation; Frequencies; Funding; Glycolates; Goals; Gynecologic Oncology; Human; Image; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; Incidence; Individual; Intraperitoneal Injections; Kinetics; Laboratories; Lead; Lesion; Ligands; Luciferases; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Minority; Modeling; Molecular; Mus; Not Hispanic or Latino; Outcome; Paclitaxel; Patients; Peritoneal; Peritoneum; Pilot Projects; Polymers; Research; Research Project Grants; Resected; Rodent; Rodent Model; System; Tennessee; Testing; The Vanderbilt-Ingram Cancer Center at the Vanderbilt University; Therapeutic Agents; Tissue Stains; Tissues; Toxic effect; Treatment Protocols; Tumor Burden; Tumor Immunity; United States National Institutes of Health; Universities; Woman; Work; anti-PD-L1; anti-PD-L1 therapy; anti-cancer; anticancer research; base; cancer health disparity; cancer immunotherapy; cancer therapy; checkpoint therapy; clinical practice; compliance behavior; controlled release; design; efficacy testing; experience; human disease; human model; immune checkpoint; immunotherapy clinical trials; improved; innovation; intraperitoneal; medical schools; mortality; mouse model; novel; objective response rate; particle; response; response biomarker; side effect; success; tool; tumor; tumor progression

PROJECT SUMMARY: PILOT RESEARCH PROJECT Immunotherapies can provide effective cancer therapy, but only in a minority of patients. The clinical success of immune checkpoint inhibitors in some malignancies has not translated to ovarian cancer. Objective response rates for single-agent immune checkpoint inhibitor (CPI) immunotherapy clinical trials in ovarian cancer are 6- 15%. Also, treated patients experience the consequences of dysregulated immunity from systemic administration of these agents. For cancers in which primary disease is accessible/resected, or in metastatic disease in which lesions are accessible, controlled release immunotherapy delivered locally may provide powerful – and systemic – anti-cancer immunity. Most anti-cancer therapies, including CPI immunotherapies, possess dose-limiting toxicities in non-target tissues that compromise outcomes. Restricting delivery of these therapeutic agents has demonstrated benefit with the reduction in cardiotoxicity and significant improvement in therapy through formulation of paclitaxel into Abraxane as a clinically powerful example. We propose to develop the first controlled release biomaterials to enable local delivery of high dose immunotherapies that would be intolerable if systemically administered. We aim to significantly improve the frequency and durability of response following CPI immunotherapy. We hypothesize that lower intraperitoneal immune checkpoint inhibitor concentration in humans, relative to rodents, contributes to the low efficacy observed for ovarian cancer immunotherapies in clinical trials. Our proposed controlled-release CPI will allow assessment in mice of the intraperitoneal dosing concentrations relevant to humans using a novel core/shell delivery system for sustained and controlled release. The overarching objective of this pilot project is to test improved response to cancer immunotherapy through sustained release of immune checkpoint ligands from biomaterials that are applied locally/regionally (not systemically). Our multi-PI complementary team aims to test this hypothesis in a rodent model of human ovarian cancer that aligns with the exploratory and feasibility objectives of this Pilot Research Project mechanism and appropriate to lead to a full competitive project within 3 years. Aim 1 will synthesize and characterize biomaterials that enable the sustained release of anti-PD-L1 and can be retained locally following intraperitoneal injection to improve immunotherapy while minimizing undesirable side effects. Aim 2 will characterize ovarian cancer progression, immune responses, toxicity and overall survival from the sustained release of anti-PD-L1 in the intraperitoneal cavity of rodent models that replicate aspects of human disease.

项目摘要：试点研究项目 免疫疗法可以提供有效的癌症治疗，但仅限于少数患者。临床成功 免疫检查点抑制剂在某些恶性肿瘤中的作用尚未转化为卵巢癌。客观反应 卵巢癌单药免疫检查点抑制剂 (CPI) 免疫治疗临床试验的比率为 6- 15%。此外，接受治疗的患者还会经历全身给药导致免疫失调的后果 这些代理。对于原发性疾病可接近/切除的癌症，或转移性疾病 病灶易于接近，局部进行的控释免疫疗法可以提供强大的系统性作用 – 抗癌免疫力。大多数抗癌疗法，包括 CPI 免疫疗法，都具有剂量限制 非靶组织中的毒性会损害结果。限制这些治疗剂的递送已 通过减少心脏毒性和显着改善治疗效果，证明了其益处 将紫杉醇配制为 Abraxane 是一个临床上有力的例子。我们建议开发第一个 控释生物材料，以实现无法耐受的高剂量免疫疗法的局部递送 如果系统地施用。我们的目标是显着提高以下响应的频率和持久性 CPI免疫治疗。我们假设腹膜内免疫检查点抑制剂浓度较低 与啮齿动物相比，人类导致卵巢癌免疫疗法的疗效较低。 临床试验。我们提出的控释 CPI 将允许在小鼠中评估腹膜内给药剂量 使用新型核/壳递送系统实现持续和受控释放，与人体相关的浓度。 该试点项目的总体目标是通过以下方式测试对癌症免疫疗法的改善反应： 从局部/区域应用的生物材料中持续释放免疫检查点配体（不是 系统地）。我们的多 PI 互补团队旨在在人类卵巢啮齿动物模型中检验这一假设 符合该试点研究项目机制的探索性和可行性目标的癌症，并且 适合在3年内形成一个完全有竞争力的项目。目标 1 将合成和表征生物材料 能够持续释放抗PD-L1，并可以在腹腔注射后局部保留 改善免疫治疗，同时最大限度地减少不良副作用。目标 2 将描述卵巢癌的特征 抗 PD-L1 持续释放导致的进展、免疫反应、毒性和总体生存率 复制人类疾病各个方面的啮齿动物模型的腹腔内。