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

项目总结。 免疫疗法已经成为许多不同癌症类型的新兴护理标准(SOC)。然而， 只有15%-20%的患者获得了持久的福利。其他限制包括系统交付的毒性 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(IrAEs)。 随着该领域向免疫/免疫和免疫方向发展，严重的、可能致命的irAEs的风险增加。 免疫/SOC联合疗法。作为肿瘤/免疫相互作用的“前线”，肿瘤免疫 微环境(时间)是免疫调节的关键场所，其中免疫细胞的种类在时间上 预测对不同免疫疗法的反应可能性。有利地调整时间的一种策略是 通过直接瘤内注射将多种免疫疗法定位于肿瘤，逆转 免疫抑制时间，同时促进抗肿瘤效应细胞免疫。这可以增强当地的 药物浓度，同时最大限度地减少全身暴露以及irAEs的可能性和严重性。对.的使用 作为癌症免疫治疗平台的生物材料提供了智能指导和调节的潜力 免疫细胞就地。我们的药物仿制的多肽纳米纤维水凝胶名为“SynerGel”，处于这一领域的前沿 领域，有能力耗尽抑制性免疫细胞，同时释放不同的因素在 在特定音量内的受控方式。这些多重能力可以减少偏离目标的毒性、剂量- 保守和靶向多种免疫途径，以解决癌症的异质性。整体而言 这一提议的假设是，瘤内注射SynerGel会导致免疫难治性肿瘤 通过多种机制对免疫介导的杀伤敏感，包括：1)优化局部 效应者/抑制者免疫细胞比率，2)免疫刺激剂的长期释放，以及3)增强 激活招募的效应器免疫细胞。我们建议提高我们的“第一代”的效能。 基于MDP的水凝胶系统通过设计一种独特的可注射的组合免疫治疗平台 模仿药物的下一代MDP水凝胶称为SynerGel，有三个目标：Aim 1将评估SynerGel 作为一个可注射的、高度可定制的癌症免疫治疗平台，能够持续提供 当时的多重免疫疗法。目标2将探索免疫机制有助于 协同凝胶介导的不良HNSCC肿瘤微环境的改善目标3将调查 将SynerGel免疫疗法与标准护理放射治疗(RT)相结合，寻求识别特定的 RT和免疫调节相结合诱导的免疫机制 通过消除化疗的需要来降低治疗的阶段性，从而减少毒性。通过成功 为了实现这些目标，我们希望澄清SynerGel可以逆转的分子/细胞机制 实体肿瘤对标准治疗和免疫调节治疗的抵抗力，并为 如何使不利的肿瘤微环境更容易受到免疫治疗的影响。

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.