Anti-viral and antileukemic T-cell therapy as prophylaxis after HSCT

描述(申请人提供)：我们提出了一种新的细胞疗法来解决半相合干细胞移植(Haplo SCT)后B系恶性肿瘤的机会性病毒感染和复发的问题。病毒感染仍然是异基因造血干细胞移植(HSCT)患者失败的重要原因。半相合(Haplo)供者移植物的接受者尤其危险，因为预防移植物抗宿主病(GvHD)所需的T细胞耗尽。抗病毒药物只对某些病毒有效，而且大多数都有明显的毒性。我们中心已经开发出一种新的方法，可以在单个培养中有效地从T细胞中扩增针对巨细胞病毒、EB病毒和腺病毒的细胞毒性T淋巴细胞(CTL)。从干细胞供体(包括Haplo供体)过继转移这些多病毒特异性CTL(MV-CTL)在体内已被证明是安全和高效的。然而，Haplo SCT后复发仍然是一个重要的问题，特别是对于B细胞恶性肿瘤患者。因此，我们设计了一种嵌合抗原受体(CAR)，将T细胞的抗原特异性重定向到B细胞系限制的细胞表面分子CD19。我们假设，过继转移供体来源的MV-CTL可以减少Haplo SCT后病毒感染和复发的发生率，这种MV-CTL是针对肿瘤细胞表达的CD19分子进行的基因修饰。在目标1中，我们将进行一项第二阶段的随机临床试验，在该临床试验中，我们将对接受了Haplo SCT的CD19-I级恶性肿瘤患者给予CAR-CD19-1-MV-CTL或不给予CTL。在目标2中，我们将描述：(I)持续的程度和持续时间以及(Ii)过继转移的CTL的抗病毒和抗白血病作用。总而言之，这些研究的结果将促进以病毒和CD19特异性CTL为靶点的HapIo SCT后MRD的发展，以提高B细胞恶性肿瘤患者的无病生存率。我们的建议是可行的，因为我们的中心拥有开发、实施和完成使用细胞和基因治疗产品的复杂生物治疗的丰富经验，并已成功赞助和实施了超过40项细胞和基因治疗研究，涉及超过25个研究人员发起的IND，包括第二阶段多中心研究。

DESCRIPTION (provided by applicant): We propose a novel cellular therapy to address the problems of opportunistic viral infection and relapse of B-lineage malignancies after haploidentical stem cell transplantation (Haplo SCT). Viral infections remain a significant cause of failure in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Recipients of Haploidentical (Haplo) donor grafts are at particular risk because of the T-cell depletion required to prevent graft versus host disease (GvHD). Antiviral drugs are effective only for some viruses, and most have significant toxicities. Our center has developed a novel approach that effectively expands cytotoxic T lymphocytes (CTL) specific for cytomegalovirus, Epstein-Barr virus and adenoviruses from T- cells in a single culture. Adoptive transfer of these multivirus-specific CTL (MV-CTL) from stem cell donors (including Haplo donors) has proved safe and highly effective in vivo. However, relapse remains a significant problem after Haplo SCT especially for patients with B-cell malignancies. Therefore, we have designed a chimeric antigen receptor (CAR) to redirect antigen specificity of T cells to the B cell lineage-restricted cell- surface molecule CD19. We hypothesize that the incidence of viral infection and relapse following Haplo SCT can be reduced by adoptively transferred donor-derived MV-CTL, genetically modified to be specific for the CD19 molecule expressed by tumor cells. In Aim 1 we will conduct a Phase II randomized clinical trial in which we will give CAR-CD19-1- MV-CTL or no CTL to patients with CD19-I- malignancies who have received a Haplo SCT. In Aim 2, we will delineate; (i) the magnitude and duration of persistence and (ii) the anti-viral and anti-leukemic effects of adoptively transferred CTL. In aggregate, the results of the studies will facilitate the evolution of targeting post-HapIo SCT MRD with viral- and CD19-specific CTLs for enhanced disease- free survival of patients with B cell malignancies. Our proposal is feasible since our center has extensive experience developing, implementing and completing complex biological therapies with cell and gene therapy products and has successfully sponsored and implemented over 40 cell and gene therapy studies under more than 25 investigator initiated INDs, including Phase II multicenter studies .