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

描述(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，加强胸腺外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预后。我之前在HSCT和恶性肿瘤的小鼠模型上进行了研究，证明了体外产生的T细胞(Pret)过继细胞疗法(Pret)促进T细胞重建的可行性和有效性。我发现，过继转移的Pret可以作为一种现成的细胞疗法，跨越MHC屏障进行管理，以增强胸腺再生和T细胞免疫。这项建议的主要目标是利用组织培养和基于组织工程的免疫治疗方法，开发增强癌症患者胸腺非依赖性T细胞重建的策略。我建议研究胸腺外部位对Pret来源的T细胞重建的贡献，并利用类似细胞外基质的三维可吸收聚合物支架开发T细胞体外和体内发育的组织结构。生物可降解聚合物的优点是可以用来构建微米或纳米纤维的三维基质，用于体内移植，并且可以通过分子定制来释放生物活性物质，从而实现高效的局部药物输送和控制细胞的生长和分化。通过将工程基质细胞-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，然后分析细胞的生长、分化、迁移和功能(包括抗肿瘤活性)，将在体外和体内研究T细胞的发育。宿主和生物材料反应的特征还将包括对植入物的血管化、生物材料降解和对植入的炎症反应的分析。根据我使用优化设计、生物材料特性和细胞-生物材料相互作用的改进组织工程方法的初步数据，我预计组织工程人工胸腺微环境的植入将导致T细胞免疫增强，并将有助于肿瘤免疫监视。在这个职业发展奖的帮助下，我在未来五年的目标是在儿科血液学/肿瘤学领域确立自己的内科科学家地位，并在一个学术中心获得终身教职。作为一名内科科学家，我希望将临床和教学活动与以实验室为基础的独立研究项目结合起来，专注于临床相关和转化性研究。

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.