Strategies to enhance thymus-independent T cell development in cancer patients

增强癌症患者胸腺独立 T 细胞发育的策略

基本信息

批准号：
8517047
负责人：
Johannes Zakrzewski
金额：
$ 12.77万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-10 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517047
关键词：
Adoptive Transfer Adult Allogenic Antigen-Presenting Cells Antigens Biocompatible Materials Blood Blood Cells Bone Marrow Bone Marrow Stem Cell Cancer Patient Cell Culture Techniques Cell Differentiation process Cell Lineage Cell Therapy Cells Chest Clinical Commit Critiques Data Development Drug Controls Drug Delivery Systems Educational process of instructing Engineering Engraftment Epithelium Extracellular Matrix Generations Gland Goals Growth Factor Hematopoietic Stem Cell Transplantation Hematopoietic stem cells High Dose Chemotherapy Immune Immune System Part Immune system Immunity Immunodeficiency and Cancer Immunologic Monitoring Immunosuppression Immunotherapeutic agent Immunotherapy Implant In Vitro Individual Infection Inflammatory Response K-Series Research Career Programs Laboratories Left Life Lymphoid Malignant Neoplasms Mature T-Lymphocyte Methods Microscopic Mus Natural regeneration Organ Outcome Patients Pediatric Hematology/Oncology Phenotype Physicians Physiological Processes Plants Polymers Positioning Attribute Property Radiation Radiation therapy Recurrence Regenerative Medicine Research Risk Scientist Signal Transduction Simulate Site Small Intestines Stem cell transplant Stromal Cells System T-Cell Development T-Lymphocyte Thymus Gland Tissue Engineering Tissues Translational Research Transplantation Tumor Immunity Vascularization Virus Diseases Writing base biocompatible polymer biodegradable polymer cancer cell cancer therapy cancer transplantation cell growth chemotherapy clinically relevant cytokine design fighting high risk implantation improved in vivo injured irradiation meetings migration mouse model nanofiber notch protein novel strategies precursor cell programs reconstitution response scaffold stem cell niche tissue culture trafficking tumor

项目摘要

DESCRIPTION (provided by applicant): The vast majority of T-cells are made in the thymus, a lymphoid organ that is particularly sensitive to radio- or chemotherapy. Strategies to enhance extrathymic T-cell development may therefore be useful to improve the outcome of conditions such as hematopoietic stem cell transplantation, cancer, immunosuppression or certain viral infections. I previously performed studies in mouse models of HSCT and malignancies demonstrating the feasibility and efficacy of adoptive cell therapy with ex vivo generated T cells (preT) to enhance T cell reconstitution. I found that adoptively transferred preT can be used as an "off-the-shelf" cell therapy and administered across MHC barriers to enhance thymic regeneration and T cell immunity. The main goal of this proposal is to develop strategies to enhance thymus independent T cell reconstitution in cancer patients, using tissue culture and tissue engineering based immunotherapeutic approaches. I propose to study the contribution of extrathymic sites to preT- derived T cell reconstitution, and to develop tissue constructs for T cell development ex vivo and in vivo using three-dimensional bioresorbable polymer scaffolds resembling extracellular matrix. Biodegradable polymers have the advantage that they can be used to fabricate micro or nanofibrous three-dimensional matrices for in vivo grafting, and they may be molecularly tailored to release bioactive agents resulting in highly effective localized drug delivery and control of cell growth and differentiation. T cell development will be studied in vitro and in vivo by implanting engineered stromal cell-polymer scaffold composites or cell-free thymic regeneration templates into mice followed by analysis of cell growth, differentiation, migration, and function (including anti-tumor activity). Characterization of host and biomaterial responses will also include analysis of vascularization of implants, biomaterial degradation, and inflammatory responses to implantation. Based on my preliminary data using an improved tissue engineering method with optimized design, biomaterial properties and cell-biomaterial interactions I expect that implantation of a tissue engineered artificial thymic microenvironment will result in enhanced T cell immunity and will contribute to tumor immunosurveillance. My goal over the next five years, with the help of this career development award, is to establish myself as a physician-scientist in the field of Pediatric Hematology/Oncology and to attain a tenure-track position at an academic center. As a physician-scientist, I hope to combine clinical and teaching activities with an independent laboratory-based research program with focus on clinically relevant and translational research.

描述（由申请人提供）：绝大多数 T 细胞是在胸腺中产生的，胸腺是一种对放射或化疗特别敏感的淋巴器官。因此，增强胸腺外 T 细胞发育的策略可能有助于改善造血干细胞移植、癌症、免疫抑制或某些病毒感染等疾病的结果。我之前在 HSCT 和恶性肿瘤的小鼠模型中进行了研究，证明了使用离体产生的 T 细胞 (preT) 进行过继细胞治疗以增强 T 细胞重建的可行性和有效性。我发现过继转移的 preT 可以用作“现成的”细胞疗法，并跨越 MHC 屏障进行施用，以增强胸腺再生和 T 细胞免疫。该提案的主要目标是制定策略，利用基于组织培养和组织工程的免疫治疗方法，增强癌症患者胸腺独立 T 细胞的重建。我建议研究胸腺外位点对前 T 衍生 T 细胞重建的贡献，并使用类似于细胞外基质的三维生物可吸收聚合物支架来开发用于离体和体内 T 细胞发育的组织构建体。可生物降解聚合物的优点是它们可用于制造用于体内移植的微米或纳米纤维三维基质，并且它们可以进行分子定制以释放生物活性剂，从而实现高效的局部药物递送和细胞生长和分化的控制。将工程基质细胞-聚合物支架复合材料或无细胞胸腺再生模板植入小鼠体内，在体外和体内研究 T 细胞发育，然后分析细胞生长、分化、迁移和功能（包括抗肿瘤活性）。宿主和生物材料反应的表征还包括植入物血管化、生物材料降解和植入的炎症反应的分析。根据我使用改进的组织工程方法和优化设计、生物材料特性和细胞-生物材料相互作用的初步数据，我预计组织工程人工胸腺微环境的植入将增强 T 细胞免疫力，并有助于肿瘤免疫监视。在这个职业发展奖的帮助下，我未来五年的目标是使自己成为儿科血液学/肿瘤学领域的医师科学家，并在学术中心获得终身职位。作为一名医师科学家，我希望将临床和教学活动与独立的基于实验室的研究项目结合起来，重点关注临床相关和转化研究。