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; 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（由申请人提供）：绝大多数T细胞都是在胸腺中制成的，胸腺是一种对放射性或化学疗法特别敏感的淋巴器官。因此，增强外激发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。我先前在HSCT和恶性肿瘤的小鼠模型中进行了研究，证明了使用过时的T细胞（PRE）（PRET）具有过养细胞治疗的可行性和功效，以增强T细胞重建。我发现，采用的PRET可以用作“现成的”细胞疗法，并在MHC障碍物上施用，以增强胸腺再生和T细胞免疫。该提案的主要目的是使用基于组织培养和基于组织工程的免疫治疗方法制定癌症患者中胸腺独立T细胞重建的策略。我建议研究外激素部位对预先衍生的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的聚合物支架来开发用于T细胞发育的组织构建体和体内的组织构建体。可生物降解的聚合物的优势是它们可用于制造微型或纳米纤维的三维矩阵，以用于体内移植，并且可以针对分子量身定制以释放生物活性剂，从而导致高效的局部药物递送和细胞生长和分化的控制。通过植入工程的基质细胞聚合物支架复合材料或无细胞的胸腺再生模板，将在体外和体内研究T细胞的发育，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将包括分析植入物的血管形成，生物材料降解以及对植入的炎症反应。根据我的初步数据，使用改进的组织工程方法，具有优化的设计，生物材料特性和细胞生物材料相互作用，我期望组织工程的人工百里香微环境植入将导致T细胞免疫，并有助于肿瘤免疫耐受性。在这一职业发展奖的帮助下，我的目标是确立自己是儿科血液学/肿瘤学领域的医生 - 科学家，并在学术中心获得终身任职地位。作为医师科学家，我希望将临床和教学活动与基于实验室的独立研究计划结合起来，重点是临床相关和转化研究。 公共卫生相关性：癌症患者，尤其是患有恶性肿瘤的高风险的癌症患者，会接受高剂量的化学疗法和放射线，有时随后进行血液或骨髓干细胞的移植，以取代或抗击患病细胞。但是，这些高危患者通常容易受到威胁生命的感染和其他并发症的伤害，因为与患病细胞一起，其T细胞在很大程度上被化学疗法和放射线消除了。 T细胞是感染和肿瘤对抗免疫细胞，在癌症治疗和移植后可能需要数月甚至数年的时间才能变得完全发挥作用。 T细胞发展出胸腺，胸腺，一个位于胸部的腺体，骨髓中未成熟的血细胞发育成T（对于“胸腺”）细胞，这些细胞在准备攻击任何看起来“异物”的细胞时释放出来。我最近开发了一种基于细胞培养的免疫疗法方法，用于治疗癌症患者和干细胞移植受者中T细胞缺乏症。我的建议旨在进一步探讨用T细胞前体免疫疗法以及组织工程的T细胞开发支持再生矩阵的潜在益处，以增强胸腺独立的T细胞重建。组织工程是旨在替代或再生受伤或患病组织或器官的再生医学领域。在一种用于组织工程的方法中，在模拟真实器官中细胞的空间排列的实验室中构建了三维支架。脚手架填充了种植健康细胞的微观孔。脚手架是由人体免疫系统耐受的材料制成的，并逐渐降解体内。我建议将这种组织工程原理应用于胸腺，旨在开发可植入的人造干细胞生态裂t，以进行T细胞的发育。人造胸腺最直接的应用是T细胞的产生，以增强干细胞移植后的免疫重建。通常，通过降低感染的风险以及癌细胞的进展，该策略对癌症患者也可能有益。 以下“批评”部分提供了基本未经编辑的审稿人的书面批评和标准评分。请注意，这些批评和标准分数是在会议之前准备的，并且在审查会议上的任何讨论之后可能没有修订。上面的“简历和摘要”部分总结了委员会的最终意见。