Experimental Therapeutics of Pediatric Hematopoietic Malignancies

该科领导新的临床试验，并与墙内和墙外的研究人员合作，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。血液病学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。最活跃的项目之一是NCI开发的抗CD22免疫毒素药物RFB4(DsFv)-PE38用于治疗耐药的急性淋巴细胞白血病(ALL)。第一代制剂(BL22，CAT-3888)的儿科I期试验是在国家癌症研究所进行的(Wayne等人，临床癌症研究报告2010；16：1894)。BL22被证明具有可接受的安全性，并且在多次复发的化疗耐药ALL的儿童中观察到了临床活动。对一种具有更高CD22结合亲和力的改良剂(moxetumomab pasudotox，HA22，CAT-8015)的研究表明，在体外对儿童ALL母细胞的细胞毒作用有所改善(Mussai等人，BR J Haematol，2010年，Epub提前印刷，2010年6月7日，PMID：20528877)。NCI、圣裘德儿童研究医院和波士顿的Dana-Farber癌症研究所/儿童医院正在进行HA22的儿科I期试验。使用这种新药物可以完全缓解化疗--难治性ALL(Wayne等人，血液2009年；114(22)：345a；Wayne等人血液2010年；116：3246a；Wayne等人血液2011年；118：1317a；Shah等人，Biol骨髓移植2012年；18(2)，Suppl 2：S234)。另一个主要的研究领域是异基因造血干细胞移植(AllSCT)治疗儿童白血病和淋巴瘤。复发仍然是异基因干细胞移植治疗儿童和青少年白血病失败的主要原因。该科研究指导同种异体抗癌反应的方法，试图增强异基因干细胞移植后移植物抗白血病的效果。该科还在一个广泛的NCI计划中发挥领导作用，该计划旨在解决allSCT后复发的问题。这些努力包括由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血液骨髓移植2010；16：564)，以及关于异基因SCT后复发的自然历史、生物学和治疗的具体研究。该科的临床试验开发活动是与一些儿科肿瘤学联合会和合作团体合作进行的，其中包括儿童肿瘤学小组和儿科血液和骨髓移植联合会。

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; Wayne et al, Blood 2010;116:3246a; Wayne et al, Blood 2011;118:1317a; Shah et al, Biol Blood Marrow Transplant 2012;18(2), Suppl 2:S234). 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.