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

SynerGel：一种用于局部免疫治疗的新型肿瘤微环境调节水凝胶

基本信息

批准号：
10681524
负责人：
Simon Young
金额：
$ 5.58万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10681524
关键词：
Activities of Daily Living Acute Address Automobile Driving Biocompatible Materials Cells Combination immunotherapy Combined Modality Therapy Data Dendritic Cells Dose Effectiveness Effector Cell Environment FDA approved Generations Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Hydrogels Immune Immune checkpoint inhibitor Immune response Immunity Immunologic Adjuvants Immunologics Immunomodulators Immunophenotyping Immunotherapeutic agent Immunotherapy In Situ Inflammatory Response Injectable Injections Intelligence Interferons Lead Lymphocyte Malignant Neoplasms Mediating Molecular Myeloid Cells Myeloid-derived suppressor cells NOS2A gene Nature Pathway interactions Patients Peptides Pharmaceutical Preparations Pre-Clinical Model Quality of life Radiation therapy Refractory Regulatory T-Lymphocyte Resistance Risk Severities Signal Transduction Solid Neoplasm Survival Rate System T cell response T memory cell T-Lymphocyte Technology Testing Toxic effect Treatment Side Effects Treatment-related toxicity Tumor-infiltrating immune cells antitumor effect base cancer immunotherapy cancer type chemotherapy cytokine cytotoxic design effective therapy exhaustion immune checkpoint blockade immune-related adverse events immunomodulatory therapies immunoregulation improved insight malignant mouth neoplasm nanofiber next generation novel novel therapeutic intervention rational design recruit response spatiotemporal standard of care systemic toxicity tumor tumor heterogeneity tumor microenvironment tumor-immune system interactions

项目摘要

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.

项目摘要。免疫疗法已成为许多不同癌症类型的新兴护理标准 (SOC)。只有 15-20% 的患者获得持久的益处。其他限制包括全身给药的毒性。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 (irAE)。随着领域转向免疫/免疫和免疫领域，严重且可能致命的 irAE 风险会增加。免疫/SOC联合治疗作为肿瘤/免疫相互作用的“前线”，肿瘤免疫。微环境（TIME）是免疫调节的关键场所，TIME 中的免疫细胞种类预测对不同免疫疗法产生反应的可能性的一种策略是有利地调节时间。通过直接瘤内递送将多种免疫治疗药物定位于肿瘤，逆转免疫抑制TIME同时促进抗肿瘤效应细胞免疫，这可以增强局部。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。生物材料作为癌症免疫治疗的平台提供了智能指导和调节的潜力我们的模拟药物肽纳米纤维水凝胶“SynerGel”处于这一领域的前沿。领域，能够耗尽抑制性免疫细胞，同时释放多种因子这些多种能力可以减少脱靶毒性、剂量。保护和靶向多种免疫途径来解决癌症的异质性。该提案的假设是肿瘤内注射 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）局部优化效应/抑制免疫细胞比率，2) 延长免疫刺激剂的释放，3) 增强我们建议提高“第一代”的功效。基于MDP的水凝胶系统，通过设计基于MDP的独特的可注射组合免疫治疗平台名为 SynerGel 的仿药物下一代 MDP 水凝胶有三个目标：目标 1 将评估 SynerGel 作为一种可注射、高度可定制的癌症免疫治疗平台，能够持续输送 TIME 的多种免疫疗法将探索有助于的免疫机制。 SynerGel 介导的 HNSCC 肿瘤微环境的不良改善将进行研究。 SynerGel 免疫疗法与标准护理放疗 (RT) 相结合，寻找特定的放疗和免疫调节相结合诱导的免疫机制，并允许有效通过消除化疗的需要来降级治疗，从而成功地降低毒性。为了实现这些目标，我们希望阐明 SynerGel 可以逆转的分子/细胞机制实体瘤对标准护理放疗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更容易受到免疫治疗的影响。