Project 1: Cell Therapy for Correction of Blood Disorders

项目1：纠正血液疾病的细胞疗法

• 批准号: 9105436
• 负责人: Rainer F. Storb
• 金额: $ 47.75万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9105436
• 关键词: AP 1903 reagent; Aplastic Anemia; Astatine; CD34 gene; Canis familiaris; Cell Therapy; Cell Transplants; Cells; Chimerism; Comorbidity; Development; Disease; Dose; Elements; Engraftment; Erythrocytes; Fanconi' s Anemia; Gene-Modified; Genetic Engineering; Goals; Graft Rejection; HLA Antigens; Half-Life; Hematological Disease; Hematopoietic; Hemoglobinopathies; Immune; Immune system; Immunologics; Infection; Infertility; Infusion procedures; Investigation; Label; Late Effects; Left; Length; Life; MabCampath; Marrow; Methods; Minority Groups; Monoclonal Antibodies; Morbidity - disease rate; Non-Malignant; Outcome; PTPRC gene; Pancytopenia; Patients; Peripheral Blood Stem Cell; Prevention; Procedures; Protocols documentation; Radioisotopes; Regimen; Resistance; Risk; Role; Safety; Second Primary Cancers; Sickle Cell Anemia; Syndrome; T-Lymphocyte; Testing; Thalassemia; Toxic effect; Transfusion; Transplantation; Transplantation Conditioning; Work; base; conditioning; curative treatments; disorder risk; ethnic minority population; fludarabine; gene therapy; graft failure; graft vs host disease; hematopoietic cell transplantation; high risk; mortality; novel; novel strategies; pre-clinical; preclinical study; prevent; protocol development; public health relevance; reconstitution; suicide gene

ABSTRACT – PROJECT 1 Hematopoietic cell transplant (HCT) is the only curative therapy for certain nonmalignant hematologic and immunologic disorders, but the risks of the procedure, namely regimen-related toxicities and complications of graft-vs.-host disease (GVHD), are considered prohibitive for many patients. Previously our group has developed regimens that essentially eliminated the risk of regimen-related mortality for most patients given HLA-matched grafts. The overall goal of Project 1 is to introduce safe and effective HCT procedures for the most challenging patients with life-threatening nonmalignant disorders: 1) those with serious co-morbidities; 2) those with inherent resistance to engraftment, such as sickle cell anemia; and 3) those with HLA- mismatched grafts. In order to accomplish this goal, we propose practice-changing strategies to eliminate short- and long-term toxicities associated with the regimen, and GVHD associated with HLA-mismatched grafts. In Specific Aim 1, we will investigate astatine-211 (211At)-anti-CD45 monoclonal antibody (MAb) to target conditioning directly to cells of the marrow and immune system. The short path length of the alpha-emitter, its very high energy, and short half-life, may reduce both early toxicities as well as late effects, such as secondary malignancies and infertility, associated with conventional conditioning agents. Non-toxic conditioning with 211At- anti-CD45 MAb will be developed for two groups of HLA-identical recipients: 1) primary immune deficiency syndromes complicated by life-threatening infections or co-morbidities, and 2) hemoglobinopathies such as sickle cell anemia or thalassemia. For patients without HLA-matched grafts, we tackle the challenge of establishing HLA-haploidentical grafts following nonmyeloablative conditioning. Accordingly, in Specific Aim 2 we seek to eliminate the risk of GVHD. We will test the hypothesis that suicide gene-modified AP1903- susceptible donor T cells (BPX 501) will aid CD34+-selected cell engraftment without the risk of GVHD. In Specific Aim 3 we propose to incorporate 211At-anti-CD45 MAb to HLA-haploidentical grafts after nonmyeloablative conditioning, a goal particularly important for sickle cell anemia patients, who are more resistant to engraftment. Ultimately, we aim to combine targeted 211At-anti-CD45 MAb conditioning with CD34+ selected grafts with BPX 501 addback as a strategy to achieve engraftment without risk of either toxic effects or GVHD. If the strategies proposed in Project 1 are successful, we will remove the most prohibitive complications of HCT, thereby giving rise to a procedure accessible to more patients. The successful development of safe HLA-haploidentical transplantation would assure that virtually every patient with a candidate disease, especially patients from ethnic minority groups, could be treated.

摘要 - 项目1 造血细胞移植（HCT）是某些非恶性血液学和 免疫障碍，但程序的风险，即与方案有关的毒性和并发症 GRAFT-VS.宿主疾病（GVHD）被认为是许多患者禁止的。以前我们的小组有 开发的方案基本上消除了大多数患者的治疗方案死亡率的风险 HLA匹配的移植物。项目1的总体目标是针对安全有效的HCT程序 大多数威胁生命的非恶性疾病的挑战者：1）患有严重合并症的挑战者； 2）那些继承了抗植物的耐药性的人，例如镰状细胞贫血； 3）那些患有hla-的人 不匹配的移植物。为了实现这一目标，我们提出了改变练习的策略以消除 与该方案相关的短期和长期毒性，以及与HLA不匹配相关的GVHD 移植物。在特定目标1中，我们将研究Astatine-211（211AT）-ANTI-CD45单克隆抗体（MAB） 直接调节骨髓和免疫系统的细胞。 alpha-Emitter的短路长度，它 非常高的能量和短期寿命可能会降低早期毒性和晚期效果，例如次要 恶性和不育，与常规调节剂有关。 211AT-无毒条件 将针对两组HLA相同的受体开发抗CD45 mAB：1）原发性免疫缺陷 威胁生命的感染或合并症以及2）血红蛋白病的综合征复杂 镰状细胞贫血或丘脑贫血。对于没有HLA匹配移植物的患者，我们应对 在非甲状腺素条件下建立HLA - 帕克洛尼族移植物。根据诉讼，在特定的目标2中 我们将测试自杀基因修饰的AP1903-的假设 易感供体T细胞（BPX 501）将有助于CD34+选择的细胞植入，而无需GVHD风险。在 具体目的3我们建议将211at-anti-cd45 mAb纳入HLA-HAPLOCINDIAL GRAFTS 非甲状腺素调节，这是对镰状细胞性贫血患者特别重要的目标，他们更多 抗植物。最终，我们的目标是将目标的211AT-ANTI-CD45 MAB条件与CD34+结合 具有BPX 501倒数倒数的选定图形作为实现植入的策略，而没有任何有毒作用的风险 或GVHD。如果项目1中提出的策略成功，我们将删除最被禁止的 HCT的并发症，从而引起更多患者可以使用的手术。成功 开发安全的HLA-HAPOLOIDTICTIC移植将假定几乎每个患有A的患者 可以治疗候选病，尤其是来自少数民族群体的患者。