CELLULAR CORRECTION OF CONGENITAL HEMATOPOIETIC DISORDERS

先天性造血障碍的细胞纠正

• 批准号: 6500777
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6500777
• 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.

当有组织兼容的供体可用时，同种异体造血干细胞移植（HSCT）提供了一种非常成功的模态，以纠正造血的先天性疾病。阻止这种方法更广泛使用的主要障碍是匹配的捐助者的可用性，特别是对于服务不足的少数民族和迅速进行性疾病的患者。在过去的五年中，我们和其他人通过试图制定有助于单倍型HSCT的策略来克服这一障碍。我们假设操纵供体T细胞诱导对受体的持久无反应性的人会增加供体池，同时可以改善与同种异体反应性相关的HSCT毒性。在我们对供体的供体T细胞抗体的体内诱导对受体的I阶段试验中，我们证明了这种方法的可行性，并成功地对2个造血性疾病的儿童成功地进行了单倍型供体HSCT。 为了使更多的造血先天性疾病患者早些时候提供这种疾病病程，我们必须改善HSCT的治疗指数。为了实现这一目标，我们必须加强同种异体匹配和单倍型供体的HSCT的我们建立的，相当大的短期和长期毒性，以与患有慢性疾病的患者的直接寿命和预期寿命和生活质量。对于这些患者而言，从根本上增加急性发病率或死亡率，也不是将一种慢性疾病代替另一种疾病是可以接受的。如果：1）每个捐赠者独有的同种异体反应性：接受者对可以特别消除治疗指数； 2）化学上治疗性骨髓性疗法的短期和长期副作用可以降低或预防； 3）HSCT后可以快速恢复免疫能力。只要不满足这些目标，风险：福利比将继续赞成更良性的姑息治疗形式，而不是HSCT的风险但治愈方法。为了实现这些目的，提出了三个具体目标。首先，我们将修改我们的方法论，以便我们能够诱导和评估供体T细胞中同源物特异性的T细胞反感，以对造血性先天性疾病的患者进行HSCT。其次，我们将在临床翻译试验中应用这种改进的方法，其目标是使所有合适的患者可用，从而降低了临床上明显的急性和/或慢性GVHD的速度，并提高了免疫机构重新组成的速度和程度。第三，我们将尝试通过探索针对造血性茎和祖细胞抗原的产生T-细胞或单克隆抗体的可行性来减少或改善高剂量化学放疗的需求，这些抗原可能能够消除造trate造血。尽管这些目标是雄心勃勃的，但我们希望在此资助期间取得很大进步。实现这些目标可能会使使用近乎普遍的供体差通过HSCT纠正造血性的先天性疾病，而不会使伴有同种异体性，免疫能力和相关方案的急性和慢性毒性使人衰弱。