Toward safe, systemic immunotherapies for treatment of metastatic disease: Developing dendritic cell-biased immunomodulators with precise control over magnitude and timing of immune stimulation

实现治疗转移性疾病的安全、系统性免疫疗法：开发树突状细胞偏向的免疫调节剂，精确控制免疫刺激的幅度和时间

• 批准号: 10305471
• 负责人: Sachin Bhagchandani
• 金额: $ 4.6万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305471
• 关键词: Agonist; Architecture; Autoimmunity; Biodistribution; Blood; Cancer Patient; Cells; Chemistry; Clinic; Clinical; Clinical Trials; Combination immunotherapy; Cream; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Disease model; Disseminated Malignant Neoplasm; Dose; Drug Delivery Systems; Drug Kinetics; Equilibrium; Evaluation; Formulation; Functional disorder; Gel; Genetically Engineered Mouse; Goals; Grant; Human; Imiquimod; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunomodulators; Immunotherapeutic agent; Immunotherapy; Investigation; Kinetics; Lead; Lesion; Ligands; Malignant Neoplasms; Metastatic Melanoma; Molecular; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Polymers; Population; Primary Neoplasm; Prodrugs; Progression-Free Survivals; Property; Ramp; Receptor Activation; Refractory; Reporter; Research; Research Project Grants; Safety; Schedule; Scheme; Site; Structure; T-Lymphocyte; TLR7 gene; Technical Expertise; Therapeutic; Therapeutic Index; Toll-like receptors; Topical application; Toxic effect; Translating; Treatment Failure; Tumor Antigens; Tumor Immunity; Work; anti-CTLA4; anti-PD1 antibodies; anti-tumor immune response; appropriate dose; cancer cell; cancer immunotherapy; cancer therapy; clinical practice; design; effective therapy; efficacy evaluation; experimental study; immune checkpoint blockade; immune-related adverse events; immunoregulation; improved; in vitro Assay; in vivo; insight; melanoma; mouse model; patient subsets; pre-clinical; resiquimod; response; small molecule; therapy development; tumor; tumor microenvironment; uptake

Project Summary On October 1st, 2015, the FDA granted accelerated approval for the combination of anti-CTLA-4 and anti-PD-1 monoclonal antibodies showing 1-year survival of 94% and 2-year survival of 88% in patients with metastatic melanoma. These treatments, collectively referred to as immune checkpoint blockade therapies (ICBs), comprise a successful class of systemic immunotherapies. Nevertheless, a major subset of patients still do not respond in the long-term to current ICBs and this failure is likely due to the inability of ICBs to generate potent cytotoxic T lymphocyte (CTL) responses against cancer antigens as well as the tolerizing effects of so-called “cold” tumors. Thus, in order to turn non-responsive cold tumors into treatable “hot” tumors, there are countless preclinical investigations exploring other immune pathways that can be pharmacologically modulated as combination immunotherapy strategies. This has resulted in more than 1800 ongoing clinical trials in the US alone looking to combine ICBs with synthetic immunomodulators (IMs) in order to improve long-term survival in cancer patients. A major unmet need with these IMs is the ability to administer multiple therapeutic doses systemically in a safe manner to effectively treat the disease in a metastatic setting. Drug delivery systems and rational dosing schedules have the potential to reduce the toxicity of such compounds that activate the immune system, and they could enable treatment of tumors that do not respond to ICBs via kinetically controlled, targeted and precisely timed delivery of immunomodulating drugs. In the F99-phase of the proposed research, Sachin Bhagchandani will leverage the control of bottlebrush polymers (BBPs) to improve cancer immunotherapy through increasing the therapeutic index of IMs by enabling precise control over the release of these compounds and targeting them to the necessary immune cell subsets in the tumor microenvironment. In the K00-phase of the proposed research, Sachin will focus on understanding immune tolerance post initial dosing of IMs in order to design appropriate dosing schemes to circumvent tolerance since these immunotherapy treatments will require repeat dosing in order to drive an antitumor immune response. The preliminary data generated with BBPs provides a strong basis to systemically deliver these IMs by tuning drug-linker chemistry and aspect ratio (F99 phase) and defining tolerance mechanisms and dosing schedules to obtain parameters that are effective in genetically engineered mouse models which are currently refractive to ICBs (K00 phase).

项目摘要 2015年10月1日，FDA批准了抗CTLA-4和抗PD-1联合治疗的加速审批。 单克隆抗体显示转移性肝癌患者的1年生存率为94%，2年生存率为88%。 黑素瘤这些治疗，统称为免疫检查点阻断疗法（ICB）， 包括一类成功的全身免疫疗法。然而，一个主要的患者子集仍然没有 在长期内对目前的ICB作出反应，这种失败可能是由于ICB无法产生有效的 细胞毒性T淋巴细胞（CTL）对癌抗原的反应以及所谓的耐受作用 “冷”肿瘤。因此，为了将无反应的冷肿瘤变成可治疗的“热”肿瘤， 探索其他免疫途径的临床前研究， 联合免疫治疗策略。这导致在美国有超过1800个正在进行的临床试验 希望将联合收割机ICB与合成免疫调节剂（IM）联合使用，以改善 癌症患者。这些IM的一个主要未满足的需求是给予多个治疗剂量的能力 以安全的方式全身施用以有效治疗转移性环境中的疾病。 药物递送系统和合理的给药方案具有降低此类药物的毒性的潜力。 化合物，激活免疫系统，他们可以使治疗肿瘤，不响应 ICBs通过动力学控制，靶向和精确定时的免疫调节药物的输送。 在拟议研究的F99阶段，Sachin Bhagchandani将利用对瓶刷的控制 聚合物（BBP）通过增加IM的治疗指数来改善癌症免疫治疗， 能够精确控制这些化合物的释放，并将它们靶向必要的免疫系统， 肿瘤微环境中的细胞亚群。 在拟议研究的K 00阶段，Sachin将专注于了解初始阶段后的免疫耐受性。 给药IM，以设计适当的给药方案，以规避耐受性，因为这些 免疫疗法治疗将需要重复给药以驱动抗肿瘤免疫应答。 使用BBP生成的初步数据为通过调优系统地提供这些IM提供了坚实的基础 药物-接头化学和纵横比（F99相），并定义耐受机制和给药方案 为了获得在目前屈光不正的基因工程小鼠模型中有效的参数， ICBs（K 00阶段）。