Pilot Project Developing immune checkpoint controlled -release biomaterials for cancer immunology

开发用于癌症免疫学的免疫检查点控释生物材料试点项目

• 批准号: 10327935
• 负责人: Anil Shanker
• 金额: $ 4.76万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327935
• 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 immunology; 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，但仅在少数患者中。临床成功的成功 某些MALIGNANCYS中的免疫检查点抑制剂尚未转化为卵巢癌。客观响应 卵巢癌中免疫抑制剂（CPI）免疫疗法临床试验的率为6- 15％。此外，经过治疗的患者经历了免疫力失调的全身性给药的后果 这些代理。对于可访问/切除的原发性疾病的癌症，或在转移性疾病中 病变是可访问的，在当地提供的受控免疫疗法可能会提供强大的系统 - 抗癌免疫组织切。大多数抗癌疗法，包括CPI免疫疗法，潜在的剂量限制 损害结果的非目标时机的毒性。限制这些治疗剂的交付 通过降低心脏毒性和通过 将紫杉醇形成为临床上有力的例子。我们建议开发第一个 受控的释放生物材料，以实现可肠道可肠道疗法的局部输送 如果系统地管理。我们旨在显着提高响应的频率和耐用性。 CPI免疫疗法。我们假设较低的腹膜腹膜免疫切解点抑制剂浓度 相对于啮齿动物，人类对卵巢癌免疫疗法的低效率有助于 临床试验。我们提出的受控释放CPI将允许在腹膜内给药的小鼠中评估 使用新型的核心/壳输送系统进行持续和控制的释放，与人类相关的浓度。 该试点项目的总体目的是通过通过 从本地/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完整团队旨在在人类卵巢的啮齿动物模型中检验这一假设 癌症与该试点研究项目机制的探索性和可行性目标保持一致 适合在3年内导致一个完整的竞争项目。 AIM 1将合成并表征生物材料 这使抗PD-L1的持续释放可以在腹膜内注射到局部保留 改善免疫疗法，同时最大程度地减少难以理解的副作用。 AIM 2将表征卵巢癌 抗PD-L1在 复制人类疾病方面的啮齿动物模型的腹膜内腔。