CELLULAR CORRECTION OF CONGENITAL HEMATOPOIETIC DISORDERS

先天性造血障碍的细胞纠正

• 批准号: 6660971
• 负责人: EVA C GUINAN
• 金额: $ 28.42万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6660971
• 关键词: T lymphocyte; anergy; biotechnology; blood treatment; bone marrow transplantation; clinical research; clinical trial phase I; congenital blood disorder; graft versus host disease; hematopoiesis; hematopoietic stem cells; histocompatibility; homologous transplantation; human subject; human therapy evaluation; isoantigen; monoclonal antibody; stem cell transplantation; transplant rejection

When a histocompatible donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) provides a highly successful modality with which to correct congenital disorders of hematopoiesis. The major barrier preventing more widespread use of this approach is the availability of a matched donor, especially for underserved minorities and patients with rapidly progressive disease. During the past five years, we and others have made significant progress in overcoming this barrier by attempting to develop strategies that will facilitate haploidentical HSCT. We hypothesized that manipulation of donor T-cells to induce long lasting unresponsiveness to recipient alloantigens would increase the donor pool while ameliorating HSCT toxicities associated with alloreactivity. In our phase I trial of ex vivo induction of donor T-cell anergy to recipient alloantigens, we demonstrated the feasibility of this approach and have successfully performed haploidentical donor HSCT in 2 children with congenital disorders of hematopoiesis. In order for greater numbers of patients with congenital disorders of hematopoiesis to be offered this modality earlier, their disease course, we must improve the therapeutic index of HSCT. To achieve this goal, we must weight the we-established and considerable short-term and long-term toxicities of HSCT from allogeneic matched and haploidentical donors against the immediate life- expectancy and quality of life of the patient with a chronic disease. For these patients, neither radically increasing acute morbidity or mortality nor substituting one chronic disease for another would be acceptable outcomes. The therapeutic index would be significantly improved if: 1) alloreactivity unique to each donor: recipient pair could be specifically eliminated; 2) short and long term side-effects of chemoradiotherapeutic myeloablative therapy could be reduced or prevented; and 3) immunocompetence could be rapidly restored after HSCT. As long as these goals are not met, the risk: benefit ratio will continue to favor the more benign forms of palliative care rather than the risky but curative approach of HSCT. To achieve these ends, three specific aims are proposed. First, we will modify our methodology such that we will be able to induce and assess alloantigen specific T-cell anergy in donor T- cells to perform HSCT for patients with congenital disorders of hematopoiesis. Second, we will apply this improved methodology in clinical translational trials with the goals of making donors available for all suitable patients, reducing the rate of clinically significant acute and/or chronic GVHD and improving the rate and degree of immunologic reconstitution. Third, we will attempt to reduce or ameliorate the need for high dose chemoradiotherapy by exploring the feasibility of generating T- cells or monoclonal antibodies directed against hematopoietic stem and progenitor cell antigens which might be able to ablate hematopoiesis. Although these aims are ambitious, we expect to make considerable progress during this funding period. Realization of these goals may make it possible to use a near universal donor poor to correct congenital diseases of hematopoiesis by HSCT without the debilitating acute and chronic toxicities which accompany allogenicity, immunocompetence, and regimen related end-organ damage.

当组织相容性供体可用时，异基因造血干细胞移植（HSCT）提供了一种非常成功的方式来纠正先天性造血障碍。阻止这种方法更广泛使用的主要障碍是匹配供体的可用性，特别是对于服务不足的少数民族和疾病迅速进展的患者。在过去的五年中，我们和其他人已经取得了重大进展，在克服这一障碍，试图制定战略，将促进单倍体相合HSCT。我们假设，操纵供体T细胞以诱导对受体同种异体抗原的长期无反应性将增加供体库，同时改善与同种异体反应性相关的HSCT毒性。在我们的I期试验中，供体T细胞对受体同种异体抗原无反应性的离体诱导，我们证明了这种方法的可行性，并已成功地进行了单倍体相合供体HSCT在2例儿童先天性造血功能障碍。 为了使更多的先天性造血功能障碍患者能够尽早接受造血干细胞移植，缩短病程，我们必须提高造血干细胞移植的治疗指数。为了实现这一目标，我们必须根据慢性疾病患者的直接预期寿命和生活质量来权衡来自同种异体匹配和单倍相合供体的HSCT的已确定的相当大的短期和长期毒性。对于这些患者，无论是急性发病率或死亡率的急剧增加，还是用一种慢性疾病替代另一种慢性疾病，都不是可接受的结局。如果：1）可以特异性消除每个供体：受体对所特有的同种异体反应性; 2）可以减少或预防放化疗清髓性治疗的短期和长期副作用; 3）HSCT后免疫活性可以迅速恢复，则治疗指数将显著提高。只要这些目标没有实现，风险：效益比将继续有利于更良性的姑息治疗形式，而不是HSCT的风险，但治愈的方法。为实现这些目标，提出了三个具体目标。首先，我们将修改我们的方法，使得我们将能够诱导和评估供体T细胞中的同种异体抗原特异性T细胞无反应性，以对患有先天性造血障碍的患者进行HSCT。其次，我们将在临床转化试验中应用这种改进的方法，目标是使所有合适的患者都能获得供体，降低临床显著的急性和/或慢性GVHD的发生率，提高免疫重建的速度和程度。第三，我们将尝试通过探索产生针对造血干细胞和祖细胞抗原的T细胞或单克隆抗体的可行性来减少或改善对高剂量放化疗的需要，所述T细胞或单克隆抗体可能能够消除造血。虽然这些目标雄心勃勃，但我们预计在这一供资期间将取得相当大的进展。这些目标的实现可能使其能够使用接近通用的供体穷人来通过HSCT纠正先天性造血疾病，而没有伴随同种异体性、免疫活性和方案相关的终末器官损伤的使人衰弱的急性和慢性毒性。