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: 10493428
• 负责人: Anil Shanker
• 金额: $ 5.93万
• 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/10493428
• 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; 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; bioluminescence imaging; 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.

项目概要：试点研究项目 免疫疗法可以提供有效的癌症治疗，但仅适用于少数患者。的临床成功 一些恶性肿瘤中的免疫检查点抑制剂尚未转化为卵巢癌。客观缓解 卵巢癌单药免疫检查点抑制剂（CPI）免疫治疗临床试验的发生率为6- 百分之十五此外，治疗的患者经历来自全身给药的免疫失调的后果 这些代理人。对于原发性疾病可接近/切除的癌症，或转移性疾病， 病变是可接近的，局部递送的控释免疫疗法可以提供强大的全身性免疫治疗。 - 抗癌免疫力大多数抗癌疗法，包括CPI免疫疗法，具有剂量限制性。 非靶组织中损害结果的毒性。限制这些治疗剂的递送具有 证明了降低心脏毒性和显著改善治疗的益处， 将紫杉醇配制成Abraxane作为临床上有力的例子。我们建议开发第一个 控释生物材料能够局部递送高剂量免疫治疗， 如果全身给药。我们的目标是显著提高响应的频率和持久性， CPI免疫疗法。我们假设，腹腔免疫检查点抑制剂浓度较低， 相对于啮齿类动物，人类导致卵巢癌免疫治疗的低疗效， 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 使用新型核/壳递送系统用于持续和受控释放，以获得与人类相关的浓度。 该试点项目的总体目标是通过以下方法测试对癌症免疫治疗的改善反应： 从局部/区域应用的生物材料持续释放免疫检查点配体（不 系统地）。我们的多PI互补团队旨在在人类卵巢癌的啮齿动物模型中测试这一假设。 符合本试点研究项目机制的探索性和可行性目标的癌症， 在三年内完成一个具有竞争力的项目。目标1将合成和表征生物材料 其能够持续释放抗PD-L1，并且可以在腹膜内注射后局部保留， 改善免疫疗法，同时最大限度地减少不良副作用。目标2将描述卵巢癌 抗PD-L1持续释放的进展、免疫应答、毒性和总生存期 复制人类疾病方面的啮齿动物模型的腹腔。