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NextGen - CHOP

下一代 - CHOP

基本信息

批准号：
10845769
负责人：
JOHN M MARIS
金额：
$ 53.77万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
2022-06-24 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10845769
关键词：
Address Adult Agreement Antigens Area Autologous B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes Back Biological Brain Neoplasms CAR T cell therapy Cancer Patient Cancer Relapse Cell Therapy Cell physiology Characteristics Child Childhood Childhood Cancer Treatment Childhood Leukemia Childhood Solid Neoplasm Clinic Clinical Clinical Research Clinical Trials Communities Complex Coupled Coupling Custom Cytometry Data Data Collection Databases Development Disease Engineering Generations Genetic Engineering Heart Hematologic Neoplasms Immune Immune Evasion Immunosuppression Immunotherapy Knowledge Learning Life Malignant Childhood Neoplasm Malignant Neoplasms Malignant lymphoid neoplasm Mass Spectrum Analysis Methods Modeling Mutation Neuroblastoma Operative Surgical Procedures Patients Pediatric Neoplasm Pediatric Oncology Plasma Cells Pre-Clinical Model Primary Neoplasm Program Development Protein Engineering Radiation Refractory Relapse Research Design Research Personnel Resistance Route Solid Solid Neoplasm Structure Surface Antigens Survival Rate Survivors System T cell therapy T-Lymphocyte Technology Testing Text Therapeutic Toxic effect Translating Vision Work Xenograft procedure bench to bedside cancer cell cancer type cellular engineering chemotherapy childhood sarcoma chimeric antigen receptor chimeric antigen receptor T cells clinical development clinical translation comorbidity data complexity data integration data sharing design diffuse midline glioma engineered T cells high risk immune checkpoint blockade improved in vivo in vivo Model manufacture neoplastic cell next generation novel phase I trial pre-clinical preclinical development programs receptor response sharing platform small molecule standard of care tumor tumor heterogeneity tumor microenvironment

项目摘要

Next Generation T cell therapies for childhood cancers [NexTGen] Current treatments fail to cure many children with solid cancers. Recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood disease. Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers. In contrast to hematologic malignancies, solid cancers are challenging due to a lack of targets, tumor heterogeneity, and hostile tumor microenvironment (TME). We posit that through advanced cellular engineering we can overcome these challenges. Our vision is that engineered T-cell therapy for childhood solid cancers will become routine within a decade. Our central hypothesis is that coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. In NexTGen, we combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T- cell function. This, along with a closely coupled clinical development program will guide the progressive engineering of T-cells to result in transformative therapies. NexTGen is composed of 6 inter-connected work-packages (WPs) with work initially focused on pediatric sarcomas and brain tumors. AIMS: WP1: To identify suitable targets for engineered T-cells. WP2: To understand the TME in pediatric solid cancers. WP3: To develop receptors and other engineering components which target tumor cells and resist or modulate the TME. WP4: To evaluate the function of engineered T-cells developed in WP3. WP5: To translate approaches from WP4 and test them in clinical studies designed for maximal impact. Cancer Grand Challenges - Full Application - 2021 WP6: To promote data sharing across all WPs. METHODS: Target discovery (WP1) and TME studies (WP2) will utilize mass spectroscopy and chip cytometry respectively. Component engineering (WP3) will use protein engineering methods. To model engineered cell function, WP4 will mostly use intact tumor models such as immune PDXs. In WP5, clinical product generation will involve autologous closed system semi-automated manufacturing. WP6 uses standard and custom databases and data sharing platforms. USE OF RESULTS: Tumor target and TME data from WP1 and 2 will be uploaded to databases developed by WP6 for widespread distribution. Engineering components from WP3 and functional data from WP4 will be available for incorporation into therapeutic T-cell strategies by the entire community. Clinical study data from WP5 should lead to registration studies, improving cure rates and mitigation of long-term toxicity to realize our Vision.

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