Bone Marrow Transplantation in Human Disease

描述（由申请人提供）：本项目于1973年启动，旨在全面研究血液和骨髓移植（BMT）作为人类疾病治疗的生物学。从那时起，BMT已被证明是一种有效的治疗方法，甚至是治疗多种影响淋巴造血系统的恶性和非恶性疾病的首选。一些问题，包括移植物抗宿主病（GVHD）、免疫缺陷、感染、调节方案毒性和无法完全根除肿瘤，限制了BMT的成功。重大进展，特别是在支持治疗领域，已经减少了许多这些问题的严重程度，但是在改善疾病控制的临床进展，同时限制GVHD，通常落后于BMT支持治疗的进展。本提案的总体目标是通过从实验室到临床的新生物学方法的翻译来改善目前BMT的艺术状态。本项目研究中产生的大部分临床试验将涉及BMT方法。然而，从该基金开始资助的移植生物学（免疫学和造血）的临床前研究中产生的概念也导致了新的非移植治疗的发展。此外，这项新提案中正在研究的几个概念，如高剂量环磷酰胺（CY）作为唯一的高剂量调理剂和治疗GVHD，都是在30多年前首次提交该资助时开始的研究中产生的。因此，该基金的标题在生物学和历史上仍然是合适的，尽管其发现将继续具有超越生物医学治疗的意义。具体来说，本提案需要验证的假设是：1)靶向肿瘤干细胞可以减少肿瘤复发；2)细胞周期抑制与生长因子联合作用可诱导肿瘤干细胞临床分化；3)在淋巴细胞恶性肿瘤中，单独大剂量CY（即不含BMT）与标准清髓调理方案加自体BMT具有相似的疗效，同时降低毒性并避免癌细胞回输；4)大剂量CY在不破坏正常造血功能的情况下，能同时减少同种异体骨髓移植后GVHD和移植物排斥反应；5)癌症疫苗增强了自体和异体环境下的癌症特异性免疫；6)免疫调节可以激活潜在的癌症特异性免疫。

DESCRIPTION (provided by applicant): This program project was initiated in 1973 as a comprehensive effort to study the biology of blood and marrow transplantation (BMT) as treatment for human disease. 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. Several issues, including graft-versus-host disease (GVHD), immunodeficiency, infections, conditioning regimen toxicities, and inability to completely eradicate tumor, have limited the successfulness of BMT. Major advances, particularly in the area of supportive care, have decreased the magnitude of many of these problems, but clinical progress in improving disease control, while at the same time limiting GVHD, has generally lagged behind advances in BMT supportive care. The overall goal of this proposal is to improve on the current state of the art in BMT by the translation of novel biologic approaches from the laboratory to the clinic. Most of the clinical trials arising from the research in this Program Project will involve BMT approaches. However, concepts stemming from ongoing preclinical studies in transplantation biology (immunology and hematopoiesis) funded by this grant since its inception, have led to the development of novel non-transplant treatments as well. Moreover, several of the concepts being studied in this new proposal, such as high-dose cyclophosphamide (CY) as the sole high-dose conditioning agent and as treatment for GVHD, have arisen from studies initiated in the first submission of this grant over 30 years ago. Thus, the grant's title remains biologically and historically appropriate, although its findings will continue to have implications beyond BMT. Specifically, the hypotheses to be tested in this proposal are: 1) targeting cancer stem cells can decrease tumor relapse; 2) the combination of cell cycle inhibition and growth factors will induce clinical differentiation of cancer stem cells; 3) high-dose CY alone (i.e., without BMT) has similar effectiveness to standard myeloablative conditioning regimens plus autologous BMT in lymphoid malignancies, while reducing toxicity and avoiding reinfusion of cancer cells; 4) high-dose CY will diminish both GVHD and graft rejection after allogeneic BMT, without ablating normal hematopoiesis; 5) cancer vaccines augment cancer specific immunity in both the autologous and allogeneic settings; 6) immunomodulation can activate latent cancer-specific immunity.