Cancer immunotherapy using injectable hydrogels for precise and tunable multidrug delivery

项目摘要 这项提议使用尖端材料科学和纳米技术方法来提高安全性和 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，部署了 免疫系统与癌症抗争，使以前无法治愈的转移性癌症得到了戏剧性的治愈。有耐心的 然而，对免疫治疗的反应是高度可变的。这在一定程度上是由于对交付的控制不足 免疫疗法，通常仅限于全身输液，在全球范围内激活免疫系统。这 控制不善会过度刺激免疫系统最容易接近的部分，产生严重的毒性，但 不能充分刺激不易获得的抗癌免疫细胞。我们建议利用一种可注射水凝胶 我们最近开发的平台可以精确地协调多种免疫疗法的局部和受控释放 药物，从而为设计有效的癌症免疫反应提供了必要的工具。免疫细胞进化 响应高度特定的时空线索，例如级联事件、化学梯度和持续 暴露在分子“危险”信号中。由于免疫细胞处理所有这些信息以确定是否 继续战斗或退出，向正确的免疫系统传递正确的提示是至关重要的 道路。我们的方法将控制线索的时机和定位，以提高研究免疫的努力 系统，并以治疗性方式部署它。我们的初步研究表明这种方法是可行的：水凝胶 联合免疫疗法(Trp2肽、IL2细胞因子、抗CD28抗体和聚(I：C)TLR3)的交付 激动剂)显著提高了免疫原性差的B16F10黑色素瘤模型的存活率，而 标准的团注失败了。因此，我们假设精确控制和局部传递癌症 免疫治疗将在安全性和有效性方面产生深远的好处。 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，使 治疗效果，同时最大限度地减少与免疫相关的毒性。我们的方法将提供一条翻译路径 期待联合疗法，否则毒性太大，不适合临床实施。我们将系统地 在局部、持续释放的情况下研究对关键免疫调节剂的免疫反应。在……里面 目标1，我们将询问特异性刺激的抗体组合的影响和潜在的协同作用 免疫系统的适应性和先天的手臂。在目标2中，我们将描述免疫系统的重新连接 由于长期接触不同的Toll样受体(TLR)激动剂。在目标3中，我们将进一步完善我们的 水凝胶平台提供精确的药物时间表，更好地模拟内源性免疫中的提示 回应。所有研究都将在小鼠癌症模型中进行，以同时评估抗癌效果 我们的免疫治疗凝胶的安全性。

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.