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: 8115617
• 负责人: Marcel R M van den Brink
• 金额: $ 58.47万
• 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/8115617
• 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. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapy with curative potential for a variety of malignant and non-malignant diseases. The recovery of T cell immunity is severely delayed after a HSCT and this is an important cause of infections and relapse of the malignancy. In this application we propose to administer precursor T cells, which we have generated in tissue culture systems, to the stem cell graft to enhance the recovery of post-transplant T cell recovery. We plan to study 1) the sites within or outside the thymus where these cells engraft, 2) assess their effects on the regeneration of the thymus, 3) develop strategies to enhance engraftment of these cells, 4) genetically engineer the precursor T cells to enhance their anti-tumor and regenerative potential, and 5) develop an artificial thymus-like organoid that can be implanted to improve T cell recovery.

描述（由申请方提供）：延迟的免疫重建，特别是T细胞缺陷，是异基因造血干细胞移植（allo-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细胞重建的策略可以显著改善allo-HSCT的总体结局。然而，目前还没有现成的这种战略。在第一个资助期内，我们进行了关于白细胞介素-7（IL-7）或角质细胞生长因子（KGF）给药以及性类固醇（化学或外科）抑制的临床前研究，在我们的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HSCT模型中进行了研究，证明了采用离体产生的前体T细胞（preT）进行过继细胞治疗以增强移植后T细胞重建的可行性和有效性。我们发现，过继转移的preT可用作“现成的”细胞疗法，并通过MHC屏障施用以增强胸腺再生和T细胞免疫。我们目前正在准备一项I期临床试验，以研究第三方脐带血来源的preT的过继转移与抗CD 19嵌合抗原受体转导的高风险ALL的allo-HSCT受者。 我们下一个资助期的提案旨在进一步探索preT过继转移的潜在益处，以及修改我们的preT细胞培养方法，以开发一种可以支持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快速重建allo-HSCT受者的T细胞免疫，（B）preT可被工程化以增强抗肿瘤活性和胸腺和胸腺外小生境的再生，以及（c）preT培养系统可被修饰以开发用于T细胞发育的人工造血小生境。我们建议在目标1中研究胸腺外位点对前T衍生的T细胞重建的贡献，导致长期胸腺再生的前T和胸腺基质的串扰，以及增强前T转移的策略。在目标2中，我们提出研究preT的基因工程以增强其抗肿瘤或（额外）胸腺再生潜力。我们还计划设计一种人工造血小生境，用于T细胞发育，可以植入以增强T细胞发育。 公共卫生相关性：异基因造血干细胞移植（HSCT）是治疗多种恶性和非恶性疾病的重要手段。HSCT后T细胞免疫的恢复严重延迟，这是感染和恶性肿瘤复发的重要原因。在本申请中，我们提出将我们在组织培养系统中产生的前体T细胞给予干细胞移植物以增强移植后T细胞恢复的恢复。我们计划研究1）这些细胞植入胸腺内或外的部位，2）评估它们对胸腺再生的影响，3）开发增强这些细胞植入的策略，4）遗传工程改造前体T细胞以增强其抗肿瘤和再生潜力，以及5）开发可以植入以改善T细胞恢复的人工胸腺样器官。