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

• 批准号: 8699163
• 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
• 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/8699163
• 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; 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; 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; migration; mouse model; nanofiber; notch protein; novel strategies; precursor cell; programs; reconstitution; response; scaffold; stem cell niche; tissue culture; trafficking; tumor

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细胞产生于胸腺，这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诸如造血干细胞移植、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，证明了使用体外生成T细胞（preT）过继细胞治疗增强T细胞重构的可行性和有效性。我发现过继性转移的preT可以作为一种“现成的”细胞疗法，并通过MHC屏障进行管理，以增强胸腺再生和T细胞免疫。本提案的主要目标是利用组织培养和组织工程为基础的免疫治疗方法，开发增强癌症患者胸腺独立T细胞重构的策略。我建议研究胸腺外部位对预T细胞重构的贡献，并使用类似细胞外基质的三维生物可吸收聚合物支架开发体外和体内T细胞发育的组织结构。生物可降解聚合物的优势在于，它们可以用来制造用于体内移植的微或纳米纤维三维基质，并且它们可以通过分子定制来释放生物活性药物，从而实现高效的局部药物递送和细胞生长和分化的控制。通过将工程化基质细胞-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，分析细胞生长、分化、迁移和功能（包括抗肿瘤活性），研究T细胞的体外和体内发育。宿主和生物材料反应的表征也将包括对植入物血管化、生物材料降解和植入物炎症反应的分析。基于我的初步数据，使用改进的组织工程方法，优化设计，生物材料特性和细胞-生物材料相互作用，我期望植入组织工程人工胸腺微环境将导致T细胞免疫增强，并有助于肿瘤免疫监测。我的目标是在未来五年，在这个职业发展奖项的帮助下，成为一名儿科血液学/肿瘤学领域的内科科学家，并在学术中心获得终身职位。作为一名医生兼科学家，我希望将临床和教学活动与独立的实验室研究项目结合起来，专注于临床相关和转化研究。