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: 8165831
• 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/8165831
• 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

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. PUBLIC HEALTH RELEVANCE: Cancer patients, in particular those with a high risk of recurrence of their malignancy, receive high doses of chemotherapy and radiation, sometimes followed by transplants of blood or bone marrow stem cells, to replace or fight off diseased cells. However, these high-risk patients often are left vulnerable to life-threatening infections and other complications because along with diseased cells their T cells have been largely wiped out by chemotherapy and radiation. T cells are infection and tumor fighting immune cells and they can take months or even years to become fully functional after cancer treatment and transplantation. T cells develop the thymus, a gland located in the chest where immature blood cells from the bone marrow develop into T (for "thymus") cells that are released when they are ready to attack any cells that look "foreign". I recently developed a cell culture-based immunotherapy method for the treatment of T cell deficiency in cancer patients and stem cell transplantation recipients. My proposal aims to further explore the potential benefits of immunotherapy with T cell precursors, as well as with tissue engineered T cell development supporting regeneration matrices, to enhance thymus independent T cell reconstitution. Tissue engineering is a field of regenerative medicine aiming at the replacement or regeneration of injured or diseased tissues or organs. In one approach to tissue engineering, a three-dimensional scaffold is constructed in the laboratory simulating the spatial arrangement of cells in the real organ. Scaffolds are filled with microscopic pores where healthy cells are planted. Scaffolds are made from a material that is tolerated by the body's immune system and that gradually degrades inside the body. I propose to apply this tissue engineering principle to the thymus, aiming at the development of an implantable artificial stem cell niche for T cell development. The most immediate application of an artificial thymus is the generation of T cells to enhance immune reconstitution after stem cell transplantation. This strategy may also be of benefit for cancer patients in general by decreasing the risk for infections as well as the progression of cancer cells. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.

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。 与公共卫生相关：癌症患者，特别是那些恶性肿瘤复发风险很高的患者，接受高剂量的化疗和放射治疗，有时还会移植血液或骨髓干细胞，以取代或击退患病细胞。然而，这些高危患者往往容易受到危及生命的感染和其他并发症的影响，因为与患病的细胞一起，他们的T细胞已经被化疗和辐射基本上消灭了。T细胞是感染和抗肿瘤的免疫细胞，在癌症治疗和移植后，它们可能需要几个月甚至几年的时间才能完全发挥功能。T细胞发育胸腺，胸腺位于胸腺，骨髓中未成熟的血细胞在胸腺发育成T(胸腺)细胞，当T细胞准备攻击任何看起来“外来”的细胞时，T细胞就会释放出来。我最近开发了一种基于细胞培养的免疫疗法，用于治疗癌症患者和干细胞移植接受者的T细胞缺乏症。我的建议旨在进一步探索T细胞前体免疫治疗的潜在好处，以及支持再生基质的组织工程化T细胞开发，以增强胸腺非依赖性T细胞重建。组织工程是再生医学的一个领域，旨在替代或再生受伤或患病的组织或器官。在组织工程的一种方法中，在实验室中构建了一个三维支架，模拟真实器官中细胞的空间排列。支架充满了微小的毛孔，在那里种植了健康的细胞。支架是由一种被人体免疫系统耐受并在体内逐渐降解的材料制成的。我建议将这一组织工程学原理应用于胸腺，旨在开发一种可植入的人造干细胞，用于T细胞的发育。人工胸腺最直接的应用是生成T细胞，以增强干细胞移植后的免疫重建。这一策略还可能通过降低感染风险和癌细胞的进展而对一般癌症患者有利。 个别评审员的书面评论和标准分数以基本上未经编辑的形式在下面的“评论”部分提供。请注意，这些批评意见和标准分数是在会议之前准备的，在审查会议上进行任何讨论后可能没有加以修订。上文“恢复和总结讨论”一节概述了委员会的最后意见。