Bone Marrow Transplantation in Human Disease

描述（由申请人提供）： 该计划项目于1973年启动，作为一项全面的努力，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，骨髓移植已被证明是有效的治疗，甚至治疗的选择，为各种恶性和非恶性疾病，影响淋巴造血系统。 移植物抗宿主病（GVHD）、免疫缺陷、感染、预处理方案毒性和不能完全根除肿瘤等问题限制了BMT的成功。 重大进展，特别是在支持性治疗领域，已经降低了许多这些问题的严重性，但在改善疾病控制方面的临床进展，同时限制GVHD，通常落后于BMT支持性治疗的进展。 该提案的总体目标是通过将新的生物学方法从实验室转化为临床来改善BMT的当前技术水平。 本计划项目研究产生的大多数临床试验将涉及BMT方法。 然而，自该拨款成立以来，该拨款资助的移植生物学（免疫学和造血）正在进行的临床前研究所产生的概念也促进了新型非移植治疗方法的开发。 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节剂和作为GVHD的治疗，都是从30多年前首次提交该补助金时开始的研究中产生的。 因此，该基金的名称在生物学和历史上仍然是适当的，尽管它的发现将继续产生超出BMT的影响。具体而言，该提案中待检验的假设是：1）靶向癌症干细胞可以减少肿瘤复发; 2）细胞周期抑制和生长因子的组合将诱导癌症干细胞的临床分化; 3）单独的高剂量CY（即，没有BMT）在淋巴恶性肿瘤中具有与标准清髓性预处理方案加自体BMT类似的有效性，同时降低毒性并避免癌细胞的再输注; 4）高剂量CY将减少同种异体BMT后的GVHD和移植物排斥，而不消融正常的造血; 5）癌症疫苗在自体和同种异体环境中均增强癌症特异性免疫; 6）免疫调节可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.