SynerGel: A Novel Tumor Microenvironment-Modulating Hydrogel for Local Immunotherapy

项目摘要。 免疫疗法已成为许多不同癌症类型的新兴标准治疗（SOC）。然而，在这方面， 只有15-20%的患者获得持久的福利。其他限制包括全身递送的 免疫调节剂可能需要频繁、高剂量并导致免疫相关不良事件（irAE）。 随着该领域向免疫/免疫和免疫治疗方向发展， 免疫/SOC组合疗法。肿瘤免疫作为肿瘤/免疫相互作用的“前线”， 微环境（TIME）是免疫调节的关键位点，其中TIME中的免疫细胞的种类 预测对不同免疫疗法的反应的可能性。一种有利地调节时间的策略是 通过直接瘤内递送将多种免疫治疗剂定位在肿瘤处， 免疫抑制TIME，同时促进抗肿瘤效应细胞免疫。这可以提高当地 药物浓度，同时最大限度地减少全身暴露以及irAE的可能性和严重程度。使用 生物材料作为癌症免疫治疗的平台， 原位免疫细胞。我们的药物模拟，肽水凝胶称为“协同凝胶”是在这方面的最前沿 场，具有消耗抑制性免疫细胞的能力，同时释放多种因子， 在特定的体积内进行控制。这些多重能力允许降低脱靶毒性，剂量- 避免和靶向多种免疫途径，以解决癌症的异质性。整体 这一建议的假设是瘤内注射SynerGel使免疫难治性肿瘤 通过多种机制对免疫介导的杀伤敏感，包括：1）优化局部 效应/抑制免疫细胞比率，2）延长免疫刺激剂的释放，和3）增强 激活募集的效应免疫细胞。我们建议改善“第一代”的效能 基于MDP的水凝胶系统，设计独特的可注射组合免疫治疗平台，基于 称为SynerGel的药物模拟下一代MDP水凝胶有三个目标：目标1将评估SynerGel 作为一种可注射的、高度可定制的癌症免疫治疗平台， 多种免疫疗法的时间。目的2将探讨免疫机制有助于 Synergel介导的不良HNSCC肿瘤微环境的改善。目标3将调查 SynerGel免疫疗法与标准治疗放射疗法（RT）相结合，寻求确定特定的 通过RT和免疫调节的组合诱导的免疫机制，并允许有效的 通过消除对化疗的需要，从而降低毒性，从而降低治疗降级。通过成功 实现这些目标，我们希望阐明SynerGel可以逆转的分子/细胞机制 实体瘤对标准RT和免疫调节治疗的耐药性，并提供了以下见解： 如何使不利的肿瘤微环境对免疫疗法更敏感。

PROJECT SUMMARY. Immunotherapy has become an emerging standard-of-care (SOC) for many different cancer types. However, only 15-20% of patients receive durable benefit. Other limitations include the toxicity of systemically-delivered immunomodulators which may require frequent, high doses and lead to immune-related adverse events (irAEs). The risk of severe, and potentially fatal, irAEs increases as the field moves towards immune/immune and immune/SOC combination therapies. As the “front line” of tumor/immune interaction, the tumor immune microenvironment (TIME) is a critical locus of immunomodulation, where the kinds of immunocytes in the TIME predict the likelihood of response to diverse immunotherapies. One strategy to favorably modulate the TIME is to localize multiple immunotherapeutics at the tumor through direct intratumoral delivery, reversing the immunosuppressive TIME while promoting anti-tumor effector cell immunity. This can enhance local concentration of drugs while minimizing systemic exposure and likelihood and severity of irAEs. The use of biomaterials as platforms for cancer immunotherapy provides the potential to intelligently direct and modulate immune cells in situ. Our drug-mimicking, peptide nanofiber hydrogel called “SynerGel” is at the forefront of this field, with the ability to deplete suppressive immune cells while simultaneously releasing diverse factors in a controlled manner within a specific volume. These multiple abilities allow for reduced off-target toxicity, dose- sparing, and targeting of multiple immune pathways to address the heterogeneous nature of cancers. The overall hypothesis of this proposal is that intratumoral injection of SynerGel renders immunologically refractory tumors sensitive to immune-mediated killing through multiple mechanisms including: 1) optimization of local effector/suppressor immunocyte ratios, 2) prolonged release of immune-stimulating agents, and 3) enhanced activation of recruited effector immunocytes. We propose to improve on the efficacy of our “first generation” MDP-based hydrogel system by designing a unique injectable, combinatorial immunotherapy platform based on the drug-mimicking next-generation MDP hydrogel called SynerGel in three aims: Aim 1 will evaluate SynerGel as an injectable, highly customizable cancer immunotherapy platform able to perform sustained delivery of multiple immunotherapeutics to the TIME. Aim 2 will explore the immunologic mechanisms contributing to SynerGel-mediated amelioration of the adverse HNSCC tumor microenvironment. Aim 3 will investigate the combination of SynerGel immunotherapy with standard-of-care radiotherapy (RT), looking to identify specific immune mechanisms induced by the combination of RT and immunomodulation, and allowing for effective therapy de-escalation by eliminating the need for chemotherapy, thus decreasing toxicity. By successfully accomplishing these aims, we hope to clarify the molecular/cellular mechanisms by which SynerGel can reverse resistance to both standard-of-care RT and immunomodulatory therapy in solid tumors and provide insights into how the adverse tumor microenvironment can be rendered more susceptible to immunotherapy.