Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse
Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse
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DOI：
10.1182/blood-2017-07-791608
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发表时间：
2018-01-04
期刊：
影响因子：
20.3
通讯作者：
Bleakley, Marie
中科院分区：
文献类型：
--
作者：
Dossa, Robson G.;Cunningham, Tanya;Bleakley, Marie
白血病复发是异基因造血干细胞移植（HCT）失败的主要原因，HCT后复发的患者预后差。有令人信服的证据表明，有效的选择性抗白血病作用，可以提供特定的次要组织相容性（H）抗原的供体T细胞。因此，从次要H抗原特异性T细胞分离的T细胞受体（TCR）代表了用于开发靶向T细胞免疫疗法以管理HCT后白血病复发的未开发资源。认识到几个要素可能对工程化T细胞免疫疗法的功效和安全性至关重要，我们开发了具有4个组分的治疗性转基因：（1）对造血限制性、白血病相关的次要H抗原HA-1具有特异性的TCR;（2）促进CD 4（+）T细胞中I类限制性TCR功能的CD 8辅助受体;（3）诱导型胱天蛋白酶9安全开关，以在毒性的情况下能够消除HA-1 TCR T细胞;和（4）CD 34-CD 20表位，以促进工程化细胞产物的选择和转移的HA-1 TCR T细胞的追踪。T细胞产物包括HA-1 TCR CD 4（+）T细胞以增强HA-1 TCR CD 8（+）T细胞的持久性和功能，并且仅包括记忆T细胞;排除初始T细胞以限制由HA-1 TCR T细胞共表达的天然TCR介导的同种异体反应性的可能性。我们描述了这种独特的免疫疗法的发展，并证明了用慢病毒载体转导的CD 4（+）和CD 8（+）T细胞对原发性白血病的功能反应，该慢病毒载体包含HA-1 TCR转基因构建体。
Leukemia relapse remains the major cause of allogeneic hematopoietic stem cell transplantation (HCT) failure, and the prognosis for patients with post-HCT relapse is poor. There is compelling evidence that potent selective antileukemic effects can be delivered by donor T cells specific for particular minor histocompatibility (H) antigens. Thus, T-cell receptors (TCRs) isolated from minor H antigen-specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage post-HCT leukemic relapse. Recognizing that several elements may be crucial to the efficacy and safety of engineered T-cell immunotherapy, we developed a therapeutic transgene with 4 components: (1) a TCR specific for the hematopoietic-restricted, leukemia-associated minor H antigen, HA-1; (2) a CD8 coreceptor to promote function of the class I-restricted TCR in CD4(+) T cells; (3) an inducible caspase 9 safety switch to enable elimination of the HA-1 TCR T cells in case of toxicity; and (4) a CD34-CD20 epitope to facilitate selection of the engineered cell product and tracking of transferred HA-1 TCR T cells. The T-cell product includes HA-1 TCR CD4(+) T cells to augment the persistence and function of the HA-1 TCR CD8(+) T cells and includes only memory T cells; naive T cells are excluded to limit the potential for alloreactivity mediated by native TCR coexpressed by HA-1 TCR T cells. We describe the development of this unique immunotherapy and demonstrate functional responses to primary leukemia by CD4(+) and CD8(+) T cells transduced with a lentiviral vector incorporating the HA-1 TCR transgene construct.