Experimental Therapeutics of Pediatric Hematopoietic Malignancies

小儿造血系统恶性肿瘤的实验治疗

• 批准号: 8554161
• 负责人: alan s wayne
• 金额: $ 80.43万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 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/8554161
• 关键词: Acute Lymphocytic Leukemia; Address; Adolescent; Adverse effects; Affinity; Allogenic; Area; BL22 immunotoxin; Binding; Biology; Blast Cell; Blood; Boston; CD22 Immunotoxin; CD22 gene; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Childhood Lymphoma; Clinical; Clinical Research; Clinical Trials; Collaborations; Conduct Clinical Trials; Dana-Farber Cancer Institute; Development; Drug resistance; Educational workshop; Extramural Activities; Failure; Generations; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hospitals; Immune; In Vitro; In complete remission; International; Investigation; Leadership; Malignant Neoplasms; Marrow; Methods; Mission; Natural History; New Agents; Normal tissue morphology; Outcome; Patients; Pediatric Oncology; Pediatric Oncology Group; Pediatrics; Phase I Clinical Trials; Prevention; Printing; Refractory; Regimen; Relapse; Research; Research Personnel; Resistance; Role; Safety; Saint Jude Children' s Research Hospital; Therapeutic; Toxic effect; Transplantation; base; cancer type; chemotherapy; cytotoxicity; improved; leukemia; leukemia/lymphoma; novel; novel strategies; novel therapeutic intervention; pre-clinical; programs; response; translational study; treatment strategy

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.

该科与校内和校外的研究人员合作，领导新的临床试验，并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针对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cd22免疫毒素药物RFB4(dsFv)-PE38在耐药急性淋巴细胞白血病（ALL）治疗中的研究。在NCI进行了第一代药物（BL22, CAT-3888）的儿科I期试验（Wayne等，clinycancer Res 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儿童中观察到临床活性。一种具有更高CD22结合亲和力的修饰剂（moxetumomab pasudotox, HA22, CAT-8015）的研究显示，对儿童ALL细胞的体外细胞毒性得到改善（Mussai等人，Br J Haematol 2010， Epub 2010年6月7日出版前，PMID: 20528877）。一项HA22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。化疗难治性ALL的完全缓解已在这种新药中实现(Wayne等人，Blood 2009;114(22):345a；Wayne等人，Blood 2010;116:3246a；Wayne等人，Blood 2011;118:1317a；Shah等人，生物骨髓移植2012；18(2)，增刊2:S234)。另一个主要研究领域是异基因造血干细胞移植（AlloSCT）治疗儿童白血病和淋巴瘤。在儿童和青少年白血病的治疗中，复发仍然是同种异体细胞移植失败的主要原因。本节探讨了指导同种异体抗癌反应的方法，试图增强同种异体移植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，该计划解决同种异体移植后复发的问题。这些努力包括nci赞助的异基因造血干细胞移植后复发的生物学、预防和治疗国际研讨会（Bishop等人，Biol Blood Marrow Transplantation 2010;16:564）和异基因造血干细胞移植后复发的自然历史、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协会和合作团体合作进行的，包括儿童肿瘤学协会和儿科血液和骨髓移植协会。