Bone Marrow Transplantation in Human Disease

骨髓移植治疗人类疾病

基本信息

批准号：
9144305
负责人：
RICHARD J JONES
金额：
$ 185.34万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-12-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144305
关键词：
Acute Myelocytic Leukemia Affect Allogenic Animals Antibiotics Area Azacitidine Biological Preservation Biology Blood Blood donor Bone Marrow Transplantation CCR5 gene Cells Characteristics Clinical Clinical Data Clinical Trials Cyclophosphamide Data Disease Disease remission Donor Selection Dose Dysmyelopoietic Syndromes Effectiveness Elderly Exhibits FLT3 inhibitor Failure Functional disorder Funding Genetic Graft Rejection Graft-Versus-Tumor Induction HIV Hematologic Neoplasms Hematological Disease Hematopoietic Cell Growth Factors Hodgkin Disease Immune Immunologic Deficiency Syndromes Immunologics Immunosuppression Immunotherapeutic agent In Vitro Infection Lymphocyte Malignant - descriptor Memory Monitor Morbidity - disease rate Multiple Myeloma Non-Malignant Organ Patient Selection Patients Population Proliferating Recovery Recurrence Regimen Registries Relapse Resistance Rest Stem cells Supportive care System T-Lymphocyte Testing Therapeutic Toxic effect Transplantation Transplantation Conditioning Underrepresented Minority Work aldehyde dehydrogenases anticancer treatment base cancer cell cancer stem cell cancer therapy clinically relevant conditioning cytotoxic effective therapy graft vs host disease human disease improved improved outcome innovation killings mortality novel novel strategies reconstitution resistance mechanism success translational study treatment choice tumor

项目摘要

DESCRIPTION (provided by applicant): This P01 was initiated in 1973 as a comprehensive effort to study the biology of blood and marrow transplantation (BMT). Since then, BMT has proven to be effective therapy, and even the treatment of choice, for a variety of malignant and nonmalignant diseases that affect the lymphohematopoietic system. A number of issues, including conditioning regimen toxicities, infections, graft-versus-host disease (GVHD), immunodeficiency, and inability to completely eradicate tumor, have limited the success of BMT over the years. Major advances, particularly in the area of supportive care, have gradually decreased the magnitude of many of these problems. However, two inter-related issues, GVHD and tumor recurrence, remain as major obstacles to successful allogeneic (allo) BMT. Translational studies funded by this P01 over the past decade have found that high-dose cyclophosphamide (Cy) early after BMT effectively generates bi-directional tolerance, even in partially HLA mismatched donor-recipient pairs in animals studies and clinically. Importantly, our clinical data demonstrating that haploidentical related donor BMT is safe and effective, producing results similar to that seen with HLA-matched alloBMT, was confirmed by a recent BMT CTN clinical trial. Additionally, although the importance of the cancer stem cell (CSC) concept has been a matter of debate because of limited data demonstrating clinical relevance, work over this P01's last funding period suggest that CSCs in a variety of hematologic malignancies are in fact the cells responsible for relapse. Accordingly, the new proposal will build on continuing work from the past funding period primarily in the areas of modulating GVHD with high-dose post-BMT Cy and targeting CSCs. Because of the effects of GVHD on relapse, the studies into modulating GVHD and targeting CSCs are highly interdependent with most Projects studying both areas. There are 5 interactive Projects and 3 Cores. The specific hypotheses to be tested in this proposal are: 1) high-dose post-transplant Cy's ability to modulate GVHD allows safe and effective mismatched BMT, making AlloBMT a feasible alternative for severe non-malignant hematologic diseases and allowing donor selection based on genetic factors other than HLA, 2)improved immunologic recovery after high-dose post-transplant Cy allows early and effective utilization of immunologic antitumor approaches, and 3) targeting CSC can decrease relapse after BMT.

描述（由申请人提供）：该P01于1973年启动，是研究血液和骨髓移植生物学（BMT）的全面努力。从那时起，BMT已被证明是有效的治疗，甚至是选择的治疗方法，用于影响影响淋巴瘤性系统的各种恶性和非恶性疾病。多年来，许多问题，包括调节方案毒性，感染，移植物抗宿主病（GVHD），免疫缺陷以及无法完全消除肿瘤的能力，这些年来限制了BMT多年来的成功。主要进步，特别是在支持护理领域，逐渐降低了许多此类问题的规模。然而，两个相互关联的问题是GVHD和肿瘤复发，仍然是成功的同种异体（Allo）BMT的主要障碍。在过去的十年中，由该P01资助的翻译研究发现，即使在动物研究和临床上，BMT之后的高剂量环磷酰胺（CY）有效产生双向耐受性，即使在部分HLA不匹配的供体 - 竞争对中也是如此。重要的是，我们的临床数据表明，与HLA匹配的AlloBMT相似的结果与HLA匹配的AlloBMT相似的结果证实了BMT CTN CTN临床试验证实，其结果与HLA匹配的AlloBMT相似。此外，尽管癌症干细胞（CSC）概念的重要性一直是争议的问题，因为数据表明临床相关性有限，但在P01的最后一个资金期间的工作表明，各种血液学恶性肿瘤中的CSC实际上是负责复发的细胞。因此，新提案将基于过去的融资期继续进行的工作，主要是在使用高剂量的BMT CY和靶向CSC的GVHD领域。由于GVHD对复发的影响，调节GVHD和靶向CSC的研究与大多数研究这两个领域的项目高度相互依存。有5个互动项目和3个核心。在该提案中要测试的特定假设是：1）移植后CY的高剂量调节能力可以使安全有效的不匹配的BMT安全，使同种抗体成为可行的替代方案，可为严重的非恶性血液学疾病造成可行的替代方案，以便基于HLA的其他遗传学恢复，并允许供体的其他疾病，允许供体的其他疾病，允许更高的遗传学恢复，2）更高的遗传学因素2）免疫学抗肿瘤方法和3）靶向CSC可以减少BMT后的复发。

项目成果

期刊论文数量（357）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of the mismatched human leukocyte antigen haplotype in two acute myelogenous leukemia relapses after haploidentical bone marrow transplantation with post-transplantation cyclophosphamide.

DOI：
10.1038/leu.2016.144
发表时间：
2016-10
期刊：
Leukemia
影响因子：
11.4
作者：
通讯作者：

Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases.

大剂量化疗后特发性高氨血症综合征：9例回顾。

DOI：
10.1016/s0002-9343(88)80239-0
发表时间：
1988
期刊：
The American journal of medicine
影响因子：
0
作者：
Mitchell,RB;Wagner,JE;Karp,JE;Watson,AJ;Brusilow,SW;Przepiorka,D;Storb,R;Santos,GW;Burke,PJ;Saral,R
通讯作者：
Saral,R

Chronic graft-versus-host disease in the rat radiation chimera. III. Immunology and immunopathology in rapidly induced models.

大鼠辐射嵌合体中的慢性移植物抗宿主病。

DOI：
10.1097/00007890-198303000-00007
发表时间：
1983
期刊：
Transplantation
影响因子：
6.2
作者：
Beschorner,WE;Tutschka,PJ;Santos,GW
通讯作者：
Santos,GW

Pharmacology of cancer chemotherapy in the older person.

DOI：
10.1016/s0749-0690(18)30188-5
发表时间：
1997-02
期刊：
Clinics in geriatric medicine
影响因子：
3.3
作者：
Sharyn D. Baker;L. Grochow
通讯作者：
Sharyn D. Baker;L. Grochow

Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome.

DOI：
10.1016/j.bbmt.2009.11.011
发表时间：
2010-04
期刊：
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子：
0
作者：
Kasamon YL;Luznik L;Leffell MS;Kowalski J;Tsai HL;Bolaños-Meade J;Morris LE;Crilley PA;O'Donnell PV;Rossiter N;Huff CA;Brodsky RA;Matsui WH;Swinnen LJ;Borrello I;Powell JD;Ambinder RF;Jones RJ;Fuchs EJ
通讯作者：
Fuchs EJ