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Bioinstructive Scaffolds for Potent and Affordable CAR-T Cell Therapy Against Brain Tumors

用于有效且经济实惠的针对脑肿瘤的 CAR-T 细胞疗法的生物指导支架

基本信息

批准号：
10800468
负责人：
Pritha Agarwalla
金额：
$ 58.8万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10800468
关键词：
Aftercare Alginates Antibodies Antigens B lymphoid malignancy Biocompatible Materials Blood Blood - brain barrier anatomy Brain Brain Neoplasms CAR T cell therapy CD276 gene CD28 gene Cells Clinic Clinical Clinical Trials Clinical Trials Design Data Development Disease Disease Progression Dose Encapsulated Engraftment Excision Generations Glioblastoma Goals Immunologics Immunosuppression Immunotherapy Implant Infusion procedures Interleukin-2 Interleukins Intraventricular Kinetics Liquid substance Malignant neoplasm of brain Mediating Medical Methods Modality Modeling Nature Non-Hodgkin&apos s Lymphoma Operative Surgical Procedures Organ Patient Isolation Patients Peripheral Blood Mononuclear Cell Phenotype Preparation Primary Brain Neoplasms Proliferating Property Public Health Publishing Radiation therapy Recurrence Recurrent tumor Resected Retroviral Vector Retroviridae Rheology Route Solid Solid Neoplasm Speed Structure Surgically-Created Resection Cavity Swelling Symptoms T cell infiltration T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Time Toxic effect Translating Translations Treatment Efficacy Viral Virus biomaterial compatibility bioscaffold cellular transduction chimeric antigen receptor chimeric antigen receptor T cells clinical application clinical translation cost density efficacy evaluation engineered T cells implantation improved in vivo innovation manufacture manufacturing process multidisciplinary neurosurgery overexpression patient population pre-clinical preclinical trial prevent response scaffold success technology platform temozolomide therapeutic target tool tumor tumor progression ventricular system

项目摘要

PROJECT SUMMARY Glioblastoma multiforme (GBM) is a fatal and difficult to treat brain tumor with a dismal median survival of less than 2 years. Standard therapy consists of surgical tumor resection, radiotherapy, and temozolomide, which only delay tumor recurrence. Recent success of CAR T cell therapy against Non-Hodgkin’s Lymphomas have gener- ated significant excitement for the application of CAR T cells in GBM and several clinical trials have demonstrated efficacy of CAR T cells in patients with GBM. However, both immunosuppression and the blood brain barrier act as major impediments limiting CAR T cell efficacy in glioblastoma. Preclinical trials with localized administration for CAR T cells via intratumoral or intraventricular routes enhance CAR T cell infiltration to brain tumor and outperforms i.v. infusions. With locoregional control, CAR T cells are infused into the resected tumor cavity, followed by repeated infusions into the ventricular system. Multiple administrations are necessary to maintain a larger dose of CAR T cells without causing toxicity and to enhance persistence of functional CAR T cells over a longer time. However, this repetitive dosing is a major obstacle to clinical translation of CAR T cells against GBM. CAR T cell manufacturing takes weeks and carries high costs - ~$500,000 per dose. The long manufacturing time creates delays of weeks to months to infuse CAR T cells to patients with rapidly progressing disease. Additionally, lengthy ex vivo manipulations create CAR T cells with heterogeneous composition and terminal differentiation, limiting their engraftment and persistence. Taken together, the many shortfalls of current CAR T cell manufacturing urgently demand development of innovative tools to reduce manufacturing time and provide optimal CAR T cell phenotype and distribution. In this proposal, we describe the application of Multifunctional Alginate Scaffold for T cell Engineering and Release (MASTER) for use in GBM. MASTER will be implanted in the surgical cavity of GBM to generate and release CAR T cells in vivo with improved efficacy and persistence. Based on significant published and preliminary data, we show that MASTER provides bio-instructive ques to activate, transduce, expand, and release fully functional CAR T cells in vivo. The scaffold includes anchored activating antibodies and interleukins to guarantee T cell activation and proliferation. Scaffold macroporosity facilitates homogeneous distribution of T cells, creates an interface for interaction between viruses and T cells, and enables in vivo release of fully functional CAR T cells. MASTER reduces CAR T manufacturing times from weeks to a single day, substantially reducing costs. We demonstrate in preliminary data and propose further that MASTER seeded with naïve PBMCs and anti-B7H3 CAR-encoding retrovirus will be implanted in the resection cavity of a brain tumor. B7H3 is overexpressed in brain tumors and serves as a promising therapeutic target for CAR T cell therapy. This approach could have enormous clinical impact by significantly reducing therapy costs and dramatically expanding the patient population benefiting from CAR T cell therapy. These studies will provide a foundational technology platform for CAR T cell manufacturing and promote widespread patient access.

项目摘要多形性胶质母细胞瘤（GBM）是一种致命且难以治疗的脑肿瘤， 2年以上。标准治疗包括手术切除肿瘤、放疗和替莫唑胺，延缓肿瘤复发。最近针对非霍奇金淋巴瘤的CAR T细胞疗法取得了成功，具有普遍意义 CAR T细胞在GBM中的应用引起了极大的兴奋，一些临床试验已经证明 CAR T细胞在GBM患者中的功效。然而，免疫抑制和血脑屏障都起作用，作为限制CAR T细胞在胶质母细胞瘤中功效的主要障碍。局部给药的临床前试验对于CAR T细胞，通过肿瘤内或脑室内途径增强CAR T细胞对脑肿瘤的浸润，优于静脉注射。通过局部控制，将CAR T细胞输注到切除的肿瘤腔中，然后反复输注到心室系统中。需要多次给药以维持更大剂量的CAR T细胞不会引起毒性，并增强功能性CAR T细胞的持久性更长的时间然而，这种重复给药是CAR T细胞针对GBM的临床转化的主要障碍。 CAR T细胞的制造需要数周时间，成本很高-每剂约50万美元。长期制造时间造成了数周至数月的延迟，无法将CAR T细胞输注给疾病迅速进展的患者。此外，长时间的离体操作产生具有异质组成和末端修饰的CAR T细胞。分化，限制其植入和持久性。总的来说，当前CAR T的许多不足之处电池制造迫切需要开发创新工具，以缩短制造时间，最佳CAR T细胞表型和分布。在这个建议中，我们描述了多功能的应用，用于GBM的T细胞工程和释放的藻酸盐支架（MASTER）。MASTER将被植入 GBM的手术腔以在体内产生和释放CAR T细胞，具有改善的功效和持久性。基于重要的出版和初步数据，我们表明，MASTER提供了生物指导性的问题，在体内激活、扩增、扩增和释放全功能的CAR T细胞。脚手架包括锚定的激活抗体和白细胞介素以保证T细胞活化和增殖。支架大孔隙促进T细胞的均匀分布，为病毒和T细胞之间的相互作用创造界面，并且能够在体内释放全功能的CAR T细胞。MASTER将CAR T的制造时间从几周到一天，大大降低了成本。我们在初步数据中证明，并进一步提出，将在切除术中植入接种幼稚PBMC和抗B7 H3 CAR编码逆转录病毒的MASTER 脑肿瘤的空洞B7 H3在脑肿瘤中过表达，并作为一个有前途的治疗靶点， CAR T细胞疗法。这种方法可以通过显着降低治疗成本来产生巨大的临床影响并显著扩大受益于CAR T细胞疗法的患者群体。这些研究将提供这是CAR T细胞制造的基础技术平台，并促进广泛的患者获取。