Enhancement of stem cell transplants using CAR.CD30-redirected T lymphocytes

描述（由申请人提供）：干细胞移植经常被用作许多预后不良的恶性血液病患者的巩固或挽救治疗。然而，疾病复发仍然是自体SCT后治疗失败的主要原因，因为缺乏由输注同种异体移植物的供体来源的免疫组分介导的移植物抗肿瘤（GVT）效应。因此，移植后无毒的“巩固治疗”的发展仍然是非常期望的目标，并且抗原/肿瘤特异性细胞毒性T淋巴细胞（CTL）的过继转移是一种有前景的方法。将嵌合抗原受体（汽车）引入T细胞允许快速产生对几乎任何表面分子特异性的效应细胞，并且显著增加了肿瘤特异性CTL的过继转移的临床适用性。我们的中心假设是，通过将ASCT与肿瘤定向CAR+ T细胞组合，应该可以保留自体SCT的上级安全性，同时添加有效的GVT组分。我们建议在接受ASCT且复发风险高的CD 30+恶性肿瘤（包括HL和ALCL）患者中检验这一假设，因为我们有一种靶向CD 30分子的新型CAR，并且迫切需要新的基于免疫的方法来预防这些患者ASCT后的疾病复发。在拟议的I期研究中，我们将解决基于CAR的疗法与ASCT的组合是否会降低与高肿瘤负荷、这种细胞疗法的肿瘤免疫逃避相关的毒性风险，以及是否用我们的新型CAR移植并在IL-15中扩展的T细胞将具有增强的持久性、扩增和体内活性。在完成这项首次人体研究后，我们将知道CAR+ T细胞的输注是否安全，以及细胞是否持续存在并具有体内功能。执行研究的所有组成部分都已到位，我们有足够的个人和机构经验，以确保研究将按计划启动，完成和分析，提供有关SCT后T细胞免疫疗法使用的有价值信息。

DESCRIPTION (provided by applicant): Stem cell transplantation is frequently used as a consolidation or salvage treatment for many patients with poor prognosis hematological malignancies. However, disease recurrence remains the major cause of treatment failure after autologous SCT, as the graft-versus-tumor (GVT) effects mediated by the donor-derived immune components infused with an allograft are lacking. Hence development of non-toxic "consolidation treatments" after transplant remains a highly desirable objective and the adoptive transfer of antigen/tumor-specific cytotoxic T lymphocytes (CTLs) is one promising approach. The introduction of chimeric antigen receptors (CARs) into T cells allows the rapid generation of effector cells specific for virtually any surface molecule and has significantly increased the clinical applicability of adoptive transfer of tumor-specific CTLs. Our central hypothesis is that y combining ASCT with tumor directed CAR+ T cells it should be possible to retain the superior safety of autologous SCT, whilst adding an effective GVT component. We propose to test this hypothesis in patients with CD30+ malignancies (including HL and ALCL) undergoing ASCT and at high risk of relapse, as we have a novel CAR targeting the CD30 molecule and new immune-based approaches are urged to prevent the diseases recurrence after ASCT in these patients. In the proposed phase I study we will address if combining CAR-based therapies with ASCT will reduce the risk of toxicities associated with high tumor burden, tumor immune evasion of this cell therapy, and if T cells grafted with our novel CAR and expended in IL-15 will have enhance persistence, expansion and in vivo activity. On completion of this first-in-man study we will know whether the infusion of CAR+ T cells is safe, and whether the cells persist and have in vivo functionality. All components to execute the study are in place and we have sufficient individual and institutional experience to ensure the study will be opened, completed and analyzed as planned, providing valuable information about the use of T cell immunotherapy after SCT.