Biomaterials for Targeted Modulation of Conventional Type 1 Dendritic Cells

用于靶向调节传统 1 型树突状细胞的生物材料

基本信息

批准号：
10696067
负责人：
Hua Wang
金额：
$ 46.44万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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：
2022-09-05 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696067
关键词：
4T1 Adjuvant Alginates Antigen Presentation Antigens Autoimmune Diseases Biocompatible Materials CAR T cell therapy CD8-Positive T-Lymphocytes Cancer Vaccines Cell Communication Cell membrane Cell surface Cells Chemicals Chemistry Communicable Diseases Cross Presentation Cytotoxic T-Lymphocytes Dendritic Cells Development Future Gel Glycoengineering Goals Homing Hour Hydrogels Immune Immune response Immunology Immunomodulators Immunotherapy In Situ In Vitro Injectable Interleukin-12 Interleukin-15 Kinetics Label Liposomes Malignant Neoplasms Mediating Membrane Metabolic Polysaccharides Process Research Role Solid Neoplasm Subcutaneous Injections Surface System T cell response T-Cell Activation T-Lymphocyte Technology Testing Time Toxic effect Tumor Antigens Vaccines Viscosity anti-cancer anti-tumor immune response antigen-specific T cells cancer immunotherapy chemokine clinical translation cytokine cytokine therapy effector T cell experimental study immune checkpoint blockade immune modulating agents immunoengineering immunogenic improved in vivo interleukin-21 lymph nodes melanoma migration nanovaccine neoantigens patient response rational design recruit response scaffold side effect success sugar targeted delivery therapy development triple-negative invasive breast carcinoma tumor tumor-immune system interactions

项目摘要

SUMMARY Immunotherapy has shown great promise to cure cancers, especially with the success of checkpoint blockades and chimeric antigen receptor (CAR) T cell therapies, but its utility is still limited by low patient response rate, poor efficacy against many solid tumors, and/or severe side effects. These issues motivate the development of new immunotherapy that can elicit potent and persistent cytotoxic T lymphocyte (CTL) responses and minimize off-target toxicity. Targeted modulation of type 1 conventional dendritic cells (cDC1s), a subset of DCs superior in antigen cross-presentation, in lymph nodes will enable optimal activation of CTL responses and result in robust immunotherapy, but has not been achieved so far. The primary goal of this project is to develop a macroscale materials-based system that integrates immune cell-homing macroporous materials with metabolic glycan labeling to achieve cDC1 recruitment, labeling, and targeting in vivo. With this material system, we aim to develop an unprecedented technology for targeted conjugation of immunomodulatory agents, including antigens, adjuvants, and cytokines, to cDC1s in lymph nodes, and further develop potent and safe cancer immunotherapy. To achieve this, an injectable macroporous biomaterial loaded with cDC1-recruiting chemokines and azido- sugars will be used to recruit and metabolically label cDC1s with chemical tags (e.g., azido group) in situ. These chemically tagged cDC1s can migrate from the biomaterial to lymph nodes for subsequent targeted conjugation of immunomodulatory agents via efficient and bioorthogonal click chemistry. Experiments will be organized around three aims. In Aim 1, injectable pore-forming alginate gels with independently tunable pore size, stiffness, viscosity, and chemokine release kinetics will be developed, and the impact of each parameter on the immune cell recruitment profile will be elucidated, in order to rationally design macroporous materials that can preferentially recruit and metabolically label cDC1s with azido groups in situ. In Aim 2, targeted delivery of tumor neoantigens and adjuvants or liposomal vaccines to azido-labeled cDC1s in lymph nodes via click chemistry will be explored, with a goal of improving neoantigen-specific CTL responses and the overall antitumor efficacy against poorly-immunogenic solid tumors. In Aim 3, targeted conjugation and surface display of immunomodulatory agents on cDC1s in lymph nodes will be explored to regulate cDC1-T cell interactions and amplify CTL responses. We hypothesize that cytokines, once conjugated, can be retained on cDC1 surface for hours to provide continuous stimulation to effector T cells during the T cell priming process. The completion of this project will lead to new immunotherapies with robust antitumor efficacy against solid tumors and reduced off-target side effects. Further, the cDC1 recruitment, labeling and targeting technology will also be promising for future development of therapies against autoimmune disorders and infectious diseases.

概括免疫疗法显示出治愈癌症的巨大前景，特别是在检查点封锁的成功之后和嵌合抗原受体（CAR）T细胞疗法，但其实用性仍然受到患者反应率低的限制，对许多实体瘤的疗效不佳，和/或严重的副作用。这些问题都在推动着发展新的免疫疗法可以引发有效且持久的细胞毒性T淋巴细胞（CTL）反应并最大限度地减少脱靶毒性。 1 型传统树突状细胞 (cDC1s)（高级 DC 的一个子集）的靶向调节在抗原交叉呈递中，在淋巴结中将能够最佳地激活 CTL 反应，并产生强大的结果免疫疗法，但迄今为止尚未实现。该项目的主要目标是开发一个宏观的基于材料的系统，将免疫细胞归巢大孔材料与代谢聚糖相结合标记以实现 CDC1 招募、标记和体内靶向。通过这个材料系统，我们的目标是开发用于免疫调节剂（包括抗原）靶向结合的前所未有的技术，佐剂和细胞因子，针对淋巴结中的cDC1，并进一步开发有效且安全的癌症免疫疗法。为了实现这一目标，一种可注射的大孔生物材料负载有cDC1招募趋化因子和叠氮基糖将用于原位招募 CDC1 并用化学标签（例如叠氮基）代谢标记 CDC1。这些化学标记的 CDC1 可以从生物材料迁移到淋巴结，以进行后续的靶向结合通过有效的生物正交点击化学来制备免疫调节剂。将组织实验围绕三个目标。在目标 1 中，可注射的成孔藻酸盐凝胶具有独立可调的孔径、硬度、将开发粘度和趋化因子释放动力学，以及每个参数对免疫的影响将阐明细胞募集概况，以便合理设计可以的大孔材料优先招募并用叠氮基原位代谢标记 CDC1。目标2，肿瘤靶向递送通过点击化学对淋巴结中叠氮基标记的 cDC1 进行新抗原和佐剂或脂质体疫苗将进行探索，目标是改善新抗原特异性 CTL 反应和整体抗肿瘤功效对抗免疫原性差的实体瘤。在目标 3 中，靶向缀合和表面展示将探索淋巴结中 cDC1 的免疫调节剂来调节 cDC1-T 细胞相互作用和放大 CTL 反应。我们假设细胞因子一旦缀合，就可以保留在 cDC1 表面上在 T 细胞启动过程中为效应 T 细胞提供持续刺激。完成该项目将带来新的免疫疗法，对实体瘤具有强大的抗肿瘤功效，并减少脱靶副作用。此外，cDC1招募、标记和靶向技术也将有望用于针对自身免疫性疾病和传染病的疗法的未来发展。