Cancer immunotherapy using injectable hydrogels for precise and tunable multidrug delivery

项目摘要 该提案使用尖端的材料科学和纳米技术方法来提高安全性， 癌症免疫治疗的有效性。一旦癌症转移，手术切除不再是一种选择， 医疗干预很少能成功治愈甚至控制这种疾病。幸运的是， 免疫系统对抗癌症已经导致以前无法治疗转移性癌症的戏剧性治愈。患者 然而，对免疫疗法的反应是高度可变的。部分原因是对交付的控制不足， 免疫疗法通常限于全身性输注，全面激活免疫系统。这 控制不力会过度刺激免疫系统最容易接触的部分，产生严重的毒性， 不充分地刺激较难接近的抗癌免疫细胞。我们建议利用可注射水凝胶 我们最近开发了一个平台，用于精确地协调多种免疫疗法的局部和控制释放。 药物，从而提供了一个重要的工具，工程有效的癌症免疫反应。免疫细胞进化 对高度特定的时空线索作出反应，如级联事件，化学梯度和持续的 暴露于分子"危险"信号。由于免疫细胞处理所有这些信息，以确定是否 无论是继续战斗还是退出战斗，都必须向右侧的免疫系统提供正确的信号 路上了我们的方法将控制线索的时间和定位，以改善研究免疫系统的努力。 系统并将其用于治疗。我们的初步研究显示了这种方法的可行性：水凝胶 联合免疫疗法（TRP 2肽、IL 2细胞因子、抗-CD 28抗体和聚（I：C）TLR 3）的递送 激动剂）显著改善了免疫原性差的B16 F10黑素瘤模型的存活率，而 标准推注失败。因此，我们假设精确控制和局部递送癌症 免疫疗法将在安全性和有效性方面产生深远的益处。 这项工作使用先进的材料科学方法来开发一种药物输送平台， 治疗效果，同时使免疫相关毒性最小化。我们的方法将提供一条转化路径 对于临床实施来说，联合治疗的毒性太大。我们将系统地 在局部缓释的背景下研究对关键免疫调节剂的免疫应答。在 目的1，我们将询问特异性刺激免疫应答的抗体组合的影响和潜在协同作用。 免疫系统的适应性和先天性武器。在目标2中，我们将描述免疫系统的重新布线 由于长期暴露于不同的Toll样受体（TLR）激动剂。在目标3中，我们将进一步完善 水凝胶平台递送精确药物时间表，更好地模拟内源性免疫中观察到的线索 应答所有研究都将在小鼠癌症模型中进行，以同时评估抗癌疗效 和安全性。

Project Summary This proposal uses cutting-edge materials science and nanotechnology approaches to improve the safety and effectiveness of cancer immunotherapy. Once cancer metastasizes, surgical removal is no longer an option and medical interventions rarely succeed to cure or even control the disease. Fortunately, therapies that deploy the immune system to fight cancer have led to dramatic cures in previously untreatable metastatic cancers. Patient response to immunotherapy is highly variable, however. This is partly due to insufficient control over delivery of immunotherapy, which is typically limited to systemic infusions that globally activate the immune system. This poor control overstimulates the most accessible parts of the immune system, producing grave toxicity, but inadequately stimulates less accessible anticancer immune cells. We propose to leverage an injectable hydrogel platform we recently developed to precisely orchestrate local and controlled release of multiple immunotherapy drugs, thereby providing an essential tool to engineer effective cancer immune responses. Immune cells evolved to respond to highly specific spatiotemporal cues, such as cascading events, chemical gradients, and sustained exposure to molecular “danger” signals. Since immune cells process all this information to determine whether to continue battling or to stand down, it is essential to deliver the correct cues to the immune system in the right way. Our approach will control both the timing and localization of cues to improve efforts to study the immune system and deploy it therapeutically. Our preliminary studies show the feasibility of this approach: hydrogel delivery of combination immunotherapy (TRP2 peptide, IL2 cytokine, anti-CD28 antibody, and poly(I:C) TLR3 agonist) dramatically improved survival in the poorly immunogenic B16F10 model of melanoma, whereas standard bolus injections failed. Therefore, we hypothesize that precisely controlled and local delivery of cancer immunotherapy will yield profound benefits in safety and efficacy. This work uses advanced materials science approaches to develop a drug delivery platform that maximizes therapeutic effects while minimizing immune-related toxicities. Our approach will provide a translational path forward for combination therapies that are otherwise too toxic for clinical implementation. We will systematically study the immune response to critical immunomodulatory agents in the context of local, sustained release. In Aim 1, we will interrogate the impact and potential synergy of antibody combinations that specifically stimulate the immune system’s adaptive and innate arms. In Aim 2, we will characterize the rewiring of the immune system due to prolonged exposure to diverse toll-like receptor (TLR) agonists. In Aim 3, we will further refine our hydrogel platform to deliver precise schedules of drug that better mimic cues seen in endogenous immune responses. All studies will be conducted in murine models of cancer to simultaneously assess anticancer efficacy and safety of our immunotherapeutic gels.