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

描述(申请人提供)：干细胞移植经常被用作许多预后不良的血液系统恶性肿瘤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，因为缺乏供者来源的免疫成分与同种异体移植物一起介导的移植物抗肿瘤(GVT)效应。因此，发展无毒的移植后“巩固治疗”仍然是一个非常理想的目标，而过继转移抗原/肿瘤特异性细胞毒性T淋巴细胞(CTL)是一种有前途的方法。通过将嵌合抗原受体(CARS)引入T细胞，可以快速产生对几乎所有表面分子具有特异性的效应细胞，并显著提高了过继转移肿瘤特异性CTL的临床适用性。我们的中心假设是，结合ASCT和肿瘤导向的CAR T细胞，应该可以保留自体SCT的优越安全性，同时增加有效的GVT成分。我们建议在接受ASCT并有高复发风险的CD30恶性肿瘤(包括HL和ALCL)患者中测试这一假设，因为我们有一种针对CD30分子的新CAR，并敦促采用新的基于免疫的方法来防止这些患者ASCT后的疾病复发。在拟议的第一阶段研究中，我们将研究基于CAR的治疗与ASCT相结合是否会降低与高肿瘤负担、肿瘤免疫逃逸相关的毒性风险，以及将我们的新型CAR移植到T细胞并在IL-15中消耗是否会增强持久性、扩张性和体内活性。在完成这项首个人的研究后，我们将知道输注CAR T细胞是否安全，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，我们拥有足够的个人和机构经验，以确保研究将按计划开始、完成和分析，为SCT后T细胞免疫疗法的使用提供有价值的信息。

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.