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

描述（由申请人提供）：我们提出一种新的细胞疗法来解决单倍体干细胞移植（Haplo SCT）后机会性病毒感染和b系恶性肿瘤复发的问题。病毒感染仍然是接受同种异体造血干细胞移植（HSCT）患者失败的一个重要原因。由于预防移植物抗宿主病（GvHD）所需的t细胞耗散，单倍相同（Haplo）供体移植物的受者特别危险。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。我们的中心开发了一种新的方法，可以在单次培养中从T细胞中有效地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，复发仍然是Haplo SCT后的一个重要问题，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细胞的抗原特异性转移到B细胞谱系限制性细胞表面分子CD19上。我们假设Haplo SCT后病毒感染和复发的发生率可以通过过继转移供体来源的MV-CTL来降低，经过基因修饰的MV-CTL对肿瘤细胞表达的CD19分子具有特异性。在Aim 1中，我们将进行一项II期随机临床试验，我们将对接受Haplo SCT的cd19 -1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)持久性的大小和持续时间以及（ii）过继转移CTL的抗病毒和抗白血病作用。总的来说，这些研究的结果将促进病毒和cd19特异性ctl靶向hapio后SCT MRD的发展，以提高B细胞恶性肿瘤患者的无病生存。我们的建议是可行的，因为我们中心在开发、实施和完成细胞和基因治疗产品的复杂生物疗法方面拥有丰富的经验，并且在超过25个研究者发起的ind下成功资助和实施了40多项细胞和基因治疗研究，包括II期多中心研究。

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 .