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

项目总结：先导研究项目 免疫疗法可以提供有效的癌症治疗，但只对少数患者有效。在临床上取得的成功 免疫检查点抑制剂在一些恶性肿瘤中并未转化为卵巢癌。客观反应 卵巢癌的单剂免疫检查点抑制物(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的免疫失调的后果。 这些特工的名字。对于原发疾病可以接近/切除的癌症，或在以下情况下转移的癌症 病变是可触及的，局部提供的控释免疫疗法可能会提供强大的和全身的 --抗癌免疫力。大多数抗癌疗法，包括CPI免疫疗法，都有剂量限制。 危害结果的非靶标组织中的毒性。限制这些治疗剂的投放 证明了减少心脏毒性和显著改善治疗的益处 将紫杉醇制成亚伯拉欣作为一个临床上强有力的例子。我们建议开发第一个 控制释放生物材料，使高剂量免疫疗法能够在当地进行，这是无法忍受的 如果是系统管理的话。我们的目标是显著提高响应跟踪的频率和持久性 CPI免疫疗法。我们假设，较低的腹膜免疫检查点抑制物浓度 与啮齿动物相比，人类是导致#年卵巢癌免疫疗法疗效低下的原因之一。 临床试验。我们建议的控制释放CPI将允许在小鼠身上评估腹膜内给药 使用一种新的核/壳递送系统进行持续和控制释放的与人体相关的浓度。 这个试点项目的主要目标是测试对癌症免疫治疗的改善反应，通过 从局部/区域应用的生物材料(不是)持续释放免疫检查点配体 系统地)。我们的多PI互补团队的目标是在人类卵巢的啮齿动物模型中测试这一假说 符合这一试点研究项目机制的探索性和可行性目标的癌症 适合在3年内完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 它能使抗PD-L1持续释放，并可在腹腔注射后局部保留 改进免疫治疗，同时将不良副作用降至最低。AIM 2将描述卵巢癌的特征 持续释放抗PD-L1的进展、免疫反应、毒性和总存活率 复制人类疾病某些方面的啮齿动物模型的腹膜腔。

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.