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

项目摘要 2015年10月1日，FDA批准加速批准抗CTLA-4和抗PD-1的组合 单抗显示转移性肿瘤患者1年生存率为94%，2年生存率为88% 黑色素瘤。这些疗法统称为免疫检查点阻断疗法(ICBS)， 包括一类成功的系统性免疫疗法。然而，一大部分患者仍然没有 对当前的ICBS做出长期反应，这种失败很可能是由于ICBS无法产生强大的 抗肿瘤抗原的细胞毒性T淋巴细胞(CTL)反应及其耐受作用 “冷”瘤。因此，为了把无反应的冷肿瘤变成可治疗的“热”肿瘤，有无数种 临床前研究探索可通过药物调节的其他免疫途径 联合免疫治疗策略。这导致了美国1800多项正在进行的临床试验 单独寻求将ICBS与合成免疫调节剂(IMS)相结合以提高患者的长期存活率 癌症患者。这些IMS尚未满足的一个主要需求是能够管理多个治疗剂 以系统安全的方式有效地治疗转移性环境中的疾病。 药物输送系统和合理的给药时间表有可能降低这种药物的毒性 激活免疫系统的化合物，它们可以治疗对癌症无效的肿瘤 ICBS通过运动控制、靶向和精确的时间递送免疫调节药物。 在拟议研究的F99阶段，Sachin Bhagchandani将利用瓶刷的控制 聚合物(BBP)通过提高IMS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，并将它们定位于必要的免疫力 肿瘤微环境中的细胞亚群。 在拟议研究的K00阶段，Sachin将专注于了解初始免疫耐受 IMS的剂量，以设计适当的剂量方案来规避耐受性，因为这些 免疫疗法将需要重复剂量，以驱动抗肿瘤免疫反应。 由BBP生成的初步数据为通过调整系统地交付这些IM提供了强有力的基础 药物连接物化学和长径比(F99相)和确定耐受机制和给药计划 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 至ICBS(K00阶段)。

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).