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.

全面的 项目概要 用于调节 GVHD 的移植后环磷酰胺 (PTCy) 的开发是我们的一个典型例子 小组成功的转化研究。 PTCy 不仅允许安全的单倍体 (haplo) 血液或 至少 75 岁的患者接受骨髓移植 (BMT)，但单倍体 BMT 与 PTCy 的结果现已得到证实 许多国际研究和登记研究似乎与匹配捐赠者的研究相似。我们组 还表明 PTCy 还允许应用安全有效的错配无关供体 BMT。 与 PTCy 相关的 GVHD 并发症的减少将非复发死亡率 (NRM) 降低至 即使在不匹配的情况下，比例也低于 10%，消除了成功同种异体的主要障碍之一 (allo) BMT，捐助者可用性。 PTCy 帮助几乎所有有需要的人开放了 alloBMT。随着减少 在NRM中，复发已成为迄今为止alloBMT的主要并发症。新出现的数据表明，一种新的非 耐受且未耗尽的移植免疫系统能够增强大多数免疫系统的活性 抗癌剂、小分子以及免疫剂。因此，该提案的主要目标是 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数据 团体，已经通过这种方法表现出了希望，也许最好的例子是令人印象深刻的结果 尽管有许多此类药物，但在使用 alloBMT 和移植后 FLT3 酪氨酸激酶抑制剂的 FLT3/ITD AML 中仍可见到 在非移植环境中表现出有限活性的药物。还有新出现的数据表明 其他药物作为单一药物通常缺乏治疗活性，例如淋巴瘤中的利妥昔单抗、Ph+ 中的 TKI 白血病和阿扎西丁治疗急性髓系白血病/骨髓增生异常综合征可能具有疗效 alloBMT 后环境中的活动。 alloBMT 后的微小残留病状态也应优化 新颖的抗肿瘤方法，因为它们将以最低的肿瘤负荷和肿瘤异质性使用。 这项新提案将建立在我们的工作基础上，证明后 alloBMT 设置提供了独特的 减少 alloBMT 后复发的环境。此外，现在几乎普遍可用 与 PTCy 相关的有利安全性和成本状况使程序得以实现，开始检查 BMT 用于独特的应用。该提案的总体目标/具体目标是：1）调查后的能力 移植维持治疗以减少 BMT 后的复发，2) 研究 alloBMT 作为增强 BMT 的平台 实体瘤的新疗法，3) 研究 alloBMT 联合 PTCy 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