Strategies to enhance immune reconstitution after bone marrow transplant

骨髓移植后增强免疫重建的策略

• 批准号: 8392564
• 负责人: Marcel R M van den Brink
• 金额: $ 4.08万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392564
• 关键词: Adoptive Transfer; Aging; Allogenic; Antigen Receptors; Apoptosis; Autoimmune Diseases; Bone Marrow Transplantation; CD19 gene; Cell Culture System; Cell Culture Techniques; Cell Therapy; Cells; Chemicals; Chimerism; Clinical; Clinical Trials; Communicable Diseases; Development; Disease; Engineering; Engraftment; Funding; Genetic; Genetic Engineering; Gonadal Steroid Hormones; Graft-Versus-Tumor Induction; HIV; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hepatitis B; Immune; Immunity; Implant; In Vitro; Individual; Infection; Interleukin-7; Ligands; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Non-Malignant; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Phase I Clinical Trials; Property; Radiation Injuries; Radio; Recovery; Rejuvenation; Relapse; Role; Site; Source; Stem cell transplant; Stem cells; System; T-Cell Development; T-Lymphocyte; Thymus Gland; Time; Tissue Engineering; Transplantation; Tumor Necrosis Factor-alpha; Umbilical Cord Blood; antimicrobial; base; cellular engineering; design; high risk; improved; in vivo; keratinocyte growth factor; mortality; novel; preclinical study; reconstitution; regenerative; tissue culture; tumor; vector

DESCRIPTION (provided by applicant): Delayed immune reconstitution, and in particular T cell deficiency, is an important contributor to morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, leading to infections and malignant relapse. Strategies to enhance post-transplant T cell reconstitution can significantly improve the overall outcome of allo-HSCT. However, at the present time such strategies are not readily available. In the first funding period we have performed preclinical studies regarding administration of interleukin-7 (IL-7) or keratinocyte growth factor (KGF), as well as inhibition of sex steroids (chemical or surgical) resulting in three clinical trials at our center. In the current (second) funding period we have performed studies in mouse HSCT models demonstrating the feasibility and efficacy of adoptive cell therapy with ex vivo generated precursor T cells (preT) to enhance post-transplant T cell reconstitution. We 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. We are currently preparing a phase I clinical trial to study the adoptive transfer of third party cord blood-derived preT transduced with an anti-CD19 chimeric antigen receptor for allo-HSCT recipients with high risk ALL. Our proposal for the next funding period aims to further explore the potential benefits of adoptive transfer of preT, as well as modify our preT cell culture method to develop an artificial implantable hematopoietic niche that can support T cell development. We hypothesize that (a) preT rapidly reconstitutes T cell immunity in allo-HSCT recipients via both thymic and extrathymic developmental pathways, (b) preT can be engineered to enhance anti-tumor activity and the regeneration of thymic and extrathymic niches and (c) the preT culture system can be modified to develop an artificial hematopoietic niche for T cell development. We propose to study in Aim 1 the contribution of extrathymic sites to preT-derived T cell reconstitution, the crosstalk of preT and thymic stroma resulting in long-term thymic regeneration, and strategies to enhance preT transfer. In Aim 2 we propose to study genetic engineering of preT to enhance their anti-tumor or (extra)thymic regenerative potential. We also plan to engineer an artificial hematopoietic niche for T cell development that can be implanted to enhance T cell development.

描述（由申请人提供）：免疫重建延迟，特别是T细胞缺乏，是导致异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation, alloc - hsct）受者发病率和死亡率的重要因素，导致感染和恶性复发。增强移植后T细胞重构的策略可以显著改善同种异体造血干细胞移植的总体结果。但是，目前还没有现成的这种战略。在第一个资助期，我们进行了关于白介素-7 （IL-7）或角质细胞生长因子（KGF）管理的临床前研究，以及性类固醇（化学或外科）的抑制，导致我们中心进行了三项临床试验。在当前（第二个）资助期内，我们在小鼠造血干细胞移植模型中进行了研究，证明了使用体外生成的前体T细胞（preT）进行过继细胞治疗以增强移植后T细胞重构的可行性和有效性。我们发现过继性转移的preT可以作为一种“现成的”细胞疗法，并且可以跨越MHC屏障来增强胸腺再生和T细胞免疫。我们目前正在准备一项I期临床试验，以研究对高风险ALL的同种异体造血干细胞移植受者采用经抗cd19嵌合抗原受体转导的第三方脐带血源性preT的过继转移。我们在下一个资助期的提案旨在进一步探索preT过继性转移的潜在益处，并修改我们的preT细胞培养方法，以开发可支持T细胞发育的人工植入式造血生态位。我们假设(a) preT通过胸腺和胸腺外发育途径在同种异体造血干细胞受体中快速重建T细胞免疫，(b) preT可以被设计成增强抗肿瘤活性和胸腺和胸腺外生态位的再生，(c) preT培养系统可以被修改以开发用于T细胞发育的人工造血生态位。我们建议在Aim 1中研究胸腺外部位对预T细胞重构的贡献，预T和胸腺基质的相互作用导致长期胸腺再生，以及增强预T转移的策略。在目标2中，我们建议研究基因工程的preT，以增强其抗肿瘤或（额外）胸腺再生潜力。我们还计划设计一种用于T细胞发育的人工造血生态位，可以通过植入来促进T细胞的发育。