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: 10468316
• 负责人: Sachin Bhagchandani
• 金额: $ 4.68万
• 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/10468316
• 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; 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; rational design; 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的加速批准 单克隆抗体显示转移性患者的1年生存率为94％，2年生存率为88％ 黑色素瘤。这些疗法，共同称为免疫障碍障碍疗法（ICB）， 包括一类成功的系统性免疫疗法。然而，主要的患者仍然没有 长期对当前的ICB负责，此失败可能是由于ICB无法产生有效的 对癌症抗原的细胞毒性T淋巴细胞（CTL）反应以及所谓的耐受作用 “冷”肿瘤。为了将无反应性冷肿瘤变成可治疗的“热”肿瘤，有无数 临床前研究探讨了其他可以在药物调制的免疫病道 联合免疫疗法策略。这导致了美国进行的1800多次正在进行的临床试验 仅寻求将ICB与合成免疫调节剂（IMS）相结合，以改善长期生存 癌症患者。这些IMS的主要未满足需求是能够管理多种治疗剂量 系统地以安全的方式有效地在转移性环境中治疗该疾病。 药物输送系统和理性给药计划有可能降低这种毒性 激活免疫系统的化合物，它们可以实现对不反应的肿瘤的治疗 ICB通过动力学控制，靶向和精确定时输送免疫调节药物。 在拟议的研究的F99阶段中，Sachin Bhagchandani将利用瓶洗手的控制 聚合物（BBP）通过增加IMS的治疗指数来改善癌症免疫疗法 能够精确控制这些化合物的释放并将其靶向必要的免疫 肿瘤微环境中的细胞子集。 在拟议的研究的K00期间，Sachin将专注于了解初始后的免疫耐受性 IMS的给药以设计适当的给药方案以规避容忍度，因为 免疫疗法治疗将需要重复给药才能驱动抗肿瘤免疫响应。 BBPS生成的初步数据为通过调谐提供了有力的基础来系统地交付这些IM 药物链链化学和纵横比（F99阶段）以及定义耐受性机制和给药时间表 获得在当前折射的基因工程鼠标模型中有效的参数 到ICB（K00阶段）。