Bone Marrow Transplantation in Human Disease

骨髓移植治疗人类疾病

• 批准号: 10671619
• 负责人: RICHARD J JONES
• 金额: $ 161.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671619
• 关键词: AIDS related cancer; Acute Myelocytic Leukemia; Adoptive Cell Transfers; Age; Allogeneic Bone Marrow Transplantation; Allogenic; Antineoplastic Agents; Autologous; Autologous Transplantation; Biology; Blood; Blood donor; Bone Marrow Transplantation; Budgets; Cell Therapy; Cells; Clinic; Complication; Cyclophosphamide; Data; Development; Environment; Excision; FLT3 gene; Funding; Goals; Grant; Guidelines; HIV; Immune system; Immunologics; Immunotherapy; Infiltration; Infrastructure; International; Laboratories; Leadership; Life; Lymphocyte; Lymphoma; Maintenance Therapy; Malignant Neoplasms; Marrow; Morbidity - disease rate; Multiple Myeloma; Non-Malignant; Outcome; Patients; Procedures; Registries; Relapse; Residual Neoplasm; Safety; Science; Second Degree Relative; Solid Neoplasm; Structure; Therapeutic; Time; Translational Research; Translations; Transplantation; Transplantation and Immune System; Tumor Burden; Tyrosine Kinase Inhibitor; Work; cancer stem cell; cost; human disease; improved outcome; leukemia; mortality; novel; novel therapeutics; post-transplant; programs; rituximab; small molecule; stem cell biology; translational study; tumor; tumor heterogeneity; virtual

Overall Project Summary The development post-transplant cyclophosphamide (PTCy) to modulate GVHD is a prime example of our group’s successful translational research. Not only does PTCy allow safe haploidentical (haplo) blood or marrow (BMT) in patients up to at least age 75, but the outcomes of haplo BMT with PTCy, confirmed by now many international as well as registry studies, appear similar to those seen with matched donors. Our group has also shown that PTCy also allows the application of safe and effective mismatched unrelated donor BMT. The reduction in GVHD complications associated with PTCy has lowered the non-relapse mortality (NRM) to less than 10% even in the mismatched setting, removing one of the major hurdles to successful allogeneic (allo) BMT, donor availability. PTCy has helped open up alloBMT to virtually anyone in need. With the reduction in NRM, relapse has become by far the major complication of alloBMT. Emerging data suggest that a new non- tolerant and non-exhausted transplanted immune system has the ability to augment the activity of most anticancer agents, small molecule as well as immunologic. Thus, the major objective of this proposal is to study maintenance therapy after alloBMT as a means to reduce relapse. In fact, our data, as well as from other groups, already appear promising with such an approach, perhaps best exemplified by the impressive results seen in FLT3/ITD AML with alloBMT and post-transplant FLT3 tyrosine kinase inhibitors despite many of these agents showing limited activity in the non-transplant setting. There are also emerging data suggesting that other agents generally lacking curative activity as single agents, such as rituximab in lymphomas, TKIs in Ph+ leukemias, and azaciditine for acute myeloid leukemia/myelodysplastic syndrom may demonstrate curative activity in the post-alloBMT setting. The minimal residual disease state post-alloBMT should also optimize novel antitumor approaches, in that they will be utilized at lowest tumor burden as well as tumor heterogeneity. This new proposal will build on our work demonstrating that the post alloBMT setting provides a unique environment for decreasing relapse after alloBMT. In addition, the now near universal availability of the procedure, enabled by the favorable safety and cost profile associated with PTCy, opens up examining BMT for unique applications. The overall goals/specific aims of this proposal are to: 1) investigate the ability of post- transplant maintenance therapy to decrease relapse after BMT, 2) study alloBMT as a platform for enhancing novel therapies for solid tumors, and 3) study whether alloBMT with PTCy can eliminate HIV.

整体 项目摘要 移植后环磷酰胺（PTCy）调节GVHD的发展是我们研究的一个主要例子。 集团成功的转化研究。PTCy不仅允许安全的单倍相合（haplo）血液， 在至少75岁的患者中进行骨髓移植（BMT），但目前证实的PTCy单倍型BMT的结局 许多国际和登记研究似乎与匹配供体的结果相似。我们集团 还表明，PTCy还允许安全有效地应用错配的无关供体BMT。 与PTCy相关的GVHD并发症的减少降低了非复发死亡率（NRM）， 即使在不匹配的情况下也低于10%，消除了成功同种异体移植的主要障碍之一。 （allo）BMT，供体可用性。PTCy帮助向几乎所有有需要的人开放了alloBMT。与减速 在NRM中，复发已成为alloBMT的主要并发症。新出现的数据表明，一个新的非- 耐受性和非耗竭的移植免疫系统具有增强大多数免疫系统活性的能力。 抗癌剂、小分子以及免疫剂。因此，这项建议的主要目的是 研究alloBMT后的维持治疗作为减少复发的手段。事实上，我们的数据，以及其他 小组，已经出现了这样一种方法，也许最好的例子是令人印象深刻的结果 在使用同种异体BMT和移植后FLT 3酪氨酸激酶抑制剂的FLT 3/ITD AML中观察到， 在非移植环境中显示有限活性的药剂。也有新的数据表明， 其他药物通常缺乏单一药物的治疗活性，如利妥昔单抗治疗淋巴瘤，TKI治疗Ph+ 白血病和阿扎胞苷治疗急性髓细胞白血病/骨髓增生异常综合征可能显示出治愈性 在alloBMT后环境中的活性。alloBMT后的最小残留疾病状态也应该优化 新型抗肿瘤方法，因为它们将在最低的肿瘤负荷和肿瘤异质性下使用。 这项新的建议将建立在我们的工作，证明后alloBMT设置提供了独特的 减少alloBMT后复发的环境。此外，现在几乎普遍提供的 通过与PTCy相关的有利的安全性和成本概况， 独特的应用。本建议的总体目标/具体目标是：1）调查后的能力， 移植维持治疗，以减少BMT后复发，2）研究alloBMT作为增强 用于实体瘤的新疗法，和3）研究具有PTCy的alloBMT是否可以消除HIV。

项目成果

Activated Allogeneic Donor-derived Marrow-infiltrating Lymphocytes Display Measurable In Vitro Antitumor Activity.

• DOI: 10.1097/cji.0000000000000256
• 发表时间: 2019-04
• 期刊: Journal of immunotherapy (Hagerstown, Md. : 1997)

FLT3-ITD Allelic Burden and Acute Promyelocytic Leukemia Risk Stratification.

• DOI: 10.3390/biology10030243
• 发表时间: 2021-03-21
• 期刊: Biology
• 影响因子: 4.2
• 作者: Li AY;Kashanian SM;Hambley BC;Zacholski K;Duong VH;El Chaer F;Holtzman NG;Gojo I;Webster JA;Norsworthy KJ;Smith BD;DeZern AE;Levis MJ;Baer MR;Kamangar F;Ghiaur G;Emadi A
• 通讯作者: Emadi A

Persistent IDH mutations are not associated with increased relapse or death in patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide.

对于接受移植后环磷酰胺的同种异体造血细胞移植的 IDH 突变急性髓系白血病患者，持续 IDH 突变与复发或死亡增加无关。

• DOI: 10.1101/2023.08.14.23294087
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Ravindra,Niveditha;Dillon,LauraW;Gui,Gege;Smith,Matthew;Gondek,LukaszP;Jones,RichardJ;Corner,Adam;Hourigan,ChristopherS;Ambinder,AlexanderJ
• 通讯作者: Ambinder,AlexanderJ

Outcome of donor-derived TAA-T cell therapy in patients with high-risk or relapsed acute leukemia post allogeneic BMT.

• DOI: 10.1182/bloodadvances.2021006831
• 发表时间: 2022-04-26
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Kinoshita, Hannah;Cooke, Kenneth R.;Grant, Melanie;Stanojevic, Maja;Cruz, C. Russell;Keller, Michael;Fortiz, Maria Fernanda;Hoq, Fahmida;Lang, Haili;Barrett, A. John;Liang, Hua;Tanna, Jay;Zhang, Nan;Shibli, Abeer;Datar, Anushree;Fulton, Kenneth;Kukadiya, Divyesh;Zhang, Anqing;Williams, Kirsten M.;Dave, Hema;Dome, Jeffrey S.;Jacobsohn, David;Hanley, Patrick J.;Jones, Richard J.;Bollard, Catherine M.
• 通讯作者: Bollard, Catherine M.

Identification of novel HLA-restricted preferentially expressed antigen in melanoma peptides to facilitate off-the-shelf tumor-associated antigen-specific T-cell therapies.

• DOI: 10.1016/j.jcyt.2021.03.001
• 发表时间: 2021-08
• 期刊: Cytotherapy
• 影响因子: 4.5
• 作者: Stanojevic M;Hont AB;Geiger A;O'Brien S;Ulrey R;Grant M;Datar A;Lee PH;Lang H;Cruz CRY;Hanley PJ;Barrett AJ;Keller MD;Bollard CM
• 通讯作者: Bollard CM