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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.

项目概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，中位生存期很低超过2年。标准治疗包括手术肿瘤切除、放射治疗和替莫唑胺，仅延缓肿瘤复发。最近，CAR T 细胞疗法在治疗非霍奇金淋巴瘤方面取得了成功，引起了广泛关注。 CAR T 细胞在 GBM 中的应用引起了极大的兴奋，多项临床试验已经证明 CAR T 细胞在 GBM 患者中的疗效。然而，免疫抑制和血脑屏障都会起作用是限制 CAR T 细胞在胶质母细胞瘤中疗效的主要障碍。局部给药的临床前试验 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，优于静脉注射输液。通过局部区域控制，CAR T 细胞被注入切除的肿瘤腔中，随后重复输注至心室系统。需要多次管理才能维持更大剂量的 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，这种重复给药是针对 GBM 的 CAR T 细胞临床转化的主要障碍。 CAR T 细胞的制造需要数周时间，并且成本高昂——每剂约 500,000 美元。漫长的制造向疾病快速进展的患者输注 CAR T 细胞的时间会导致数周至数月的延迟。此外，长时间的离体操作创造出具有异质成分和末端的 CAR T 细胞。分化，限制了它们的植入和持久性。综合来看，目前CAR T存在诸多不足电池制造迫切需要开发创新工具来缩短制造时间并提供最佳的 CAR T 细胞表型和分布。在这个提案中，我们描述了多功能的应用用于 T 细胞工程和释放 (MASTER) 的藻酸盐支架，用于 GBM。 MASTER将被植入 GBM 的手术腔在体内生成和释放 CAR T 细胞，具有更高的功效和持久性。根据已发表的重要数据和初步数据，我们表明 MASTER 提供了生物指导性问题在体内激活、转导、扩增和释放功能齐全的 CAR T 细胞。脚手架包括锚固激活抗体和白介素，保证 T 细胞活化和增殖。支架大孔率促进 T 细胞的均匀分布，创建病毒和 T 细胞之间相互作用的界面，并能够在体内释放功能齐全的 CAR T 细胞。 MASTER 将 CAR T 制造时间缩短几周到一天，大大降低了成本。我们用初步数据证明并进一步提出接种初始 PBMC 和抗 B7H3 CAR 编码逆转录病毒的 MASTER 将被植入切除区域脑肿瘤的空腔。 B7H3 在脑肿瘤中过度表达，可作为脑肿瘤的有希望的治疗靶点 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大幅扩大受益于 CAR T 细胞疗法的患者群体。这些研究将提供 CAR T 细胞制造的基础技术平台，并促进广泛的患者获取。