Experimental Therapeutics of Pediatric Hematopoietic Malignancies

该科领导新的临床试验，并与校内和校外研究人员合作，对白血病和淋巴瘤的生物学进行相关的生物学研究和临床前调查。血液病科研究计划的一个主要重点是开发儿童白血病和淋巴瘤的靶向药物。其中最活跃的项目是NCI开发的抗CD 22免疫毒素剂RFB 4（dsFv）-PE 38在耐药性急性淋巴细胞白血病（ALL）治疗中的研究。在NCI进行了第一代药剂（BL 22，CAT-3888）的儿科I期试验（韦恩（Wayne）等人，临床癌症研究（Clin Cancer Res）2010;16：1894）。BL 22显示出可接受的安全性特征，并且在患有多次复发化疗耐药ALL的儿童中观察到临床活性。对具有更高CD 22结合亲和力的修饰剂（莫昔单抗pasudotox，HA 22，CAT-8015）的研究显示，对儿童ALL母细胞的体外细胞毒性有所改善（Mussai et al，Br J Haematol 2010，Epub ahead of print 2010 Jun 7，PMID：20528877）。HA 22的儿科I期试验正在NCI，St. Jude儿童研究医院和波士顿Dana-Farber癌症研究所/儿童医院进行。用这种新药剂已经实现了化疗难治性ALL的完全缓解（韦恩等人，血液2009;114（22）：345 a）。 研究的另一个主要领域是用于儿科白血病和淋巴瘤的异基因造血干细胞移植（AlloSCT）。复发仍然是AlloSCT治疗儿童和青少年白血病失败的主要原因。本节研究了指导同种异体抗癌反应的方法，试图增强AlloSCT后的移植物抗白血病效应。该科还在广泛的NCI计划中发挥领导作用，该计划解决了AlloSCT后复发的问题。这些努力包括NCI赞助的关于异基因造血干细胞移植后复发的生物学、预防和治疗的国际研讨会（Bishop等人，Biol Blood Marrow Transplant 2010;16：564）以及自然史、生物学的具体研究和AlloSCT后复发的治疗。 该科的临床试验开发活动是与许多儿科肿瘤学联盟和合作小组合作进行的，包括儿童肿瘤学小组和儿科血液和骨髓移植联盟。

The Section leads novel clinical trials and conducts correlative biologic studies and pre-clinical investigations into the biology of leukemias and lymphomas in collaboration with intramural and extramural investigators. A major focus of the Hematologic Diseases Section research program is the development of targeted agents for childhood leukemias and lymphomas. Among the most active programs is the study of anti-CD22 immunotoxin agents RFB4(dsFv)-PE38 developed at the NCI in the therapy of drug-resistant acute lymphoblastic leukemia (ALL). A pediatric Phase I trial of a first-generation agent (BL22, CAT-3888) was conducted at the NCI (Wayne et al, Clin Cancer Res 2010;16:1894). BL22 was shown to have an acceptable safety profile and clinical activity was observed in children with multiply relapsed chemotherapy resistant ALL. Studies of a modified agent with higher CD22 binding affinity (moxetumomab pasudotox, HA22, CAT-8015) showed improved in vitro cytotoxicity against childhood ALL blasts (Mussai et al, Br J Haematol 2010, Epub ahead of print 2010 Jun 7, PMID: 20528877). A pediatric Phase I trial of HA22 is in progress at the NCI, St. Jude Childrens Research Hospital, and the Dana-Farber Cancer Institute/Childrens Hospital, Boston. Complete remissions in chemotherapy-refractory ALL have been achieved with this new agent (Wayne et al, Blood 2009;114(22):345a). Another major area of investigation is in allogeneic hematopoietic stem cell transplantation (AlloSCT) for pediatric leukemias and lymphomas. Relapse remains a major cause of failure of AlloSCT in the treatment of children and adolescents with leukemia. The Section investigates methods to direct allogeneic anti-cancer responses in attempt to enhance graft-versus-leukemia effects after AlloSCT. The Section also serves in a leadership role in a broad NCI program that addresses the problem of relapse after AlloSCT. These efforts include an NCI-sponsored International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation (Bishop et al, Biol Blood Marrow Transplant 2010;16:564) and specific studies of the natural history, biology, and treatment of relapse after AlloSCT. The clinical trial development activities of the Section are conducted in collaboration with a number of pediatric oncology consortia and cooperative groups including the Childrens Oncology Group and the Pediatric Blood and Marrow Transplant Consortium.