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

使用 CAR.CD30 重定向 T 淋巴细胞增强干细胞移植

基本信息

批准号：
9104935
负责人：
Barbara Savoldo
金额：
$ 44.04万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104935
关键词：
Address Adjuvant Therapy Adoptive Transfer Aftercare Allografting Antibodies Antigen Receptors Antigen Targeting Antigens Autologous Autologous Stem Cell Transplantation Avidity Binding Biological Bulky Disease CD30 Antigens Cell Culture Techniques Cell Line Cells Clinical Cytotoxic T-Lymphocytes Development Disease Documentation Effector Cell Ensure Environment Generations Graft-Versus-Tumor Induction Health Hematologic Neoplasms Hodgkin Disease Immune Immune system Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Individual Infusion procedures Interleukin-15 Lymphoid Lymphoma Lytic Malignant Neoplasms Mediating Molecular Profiling Monitor Non-Hodgkin&apos s Lymphoma Pathway interactions Patients Phase I Clinical Trials Recruitment Activity Recurrence Refractory Refractory Disease Regulatory T-Lymphocyte Relapse Residual state Resistance Retroviridae Risk Safety Site Stem cell transplant Surface T cell therapy T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte TNFRSF8 gene Testing Toxic effect Transplantation Treatment Failure Tumor Antigens Tumor Burden Tumor Lysis Syndrome arm base burden of illness clinical application cytokine cytotoxic density experience high risk in vivo man neoplastic cell novel outcome forecast phase 1 study prevent receptor reconstitution success tumor tumor microenvironment

项目摘要

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.

描述（由申请人提供）：干细胞移植经常用作许多预后血液系统恶性肿瘤患者的巩固或挽救治疗。然而，由于缺乏由供体衍生的免疫成分介导的，疾病复发仍然是自体SCT后治疗失败的主要原因。因此，移植后无毒的“巩固处理”的发展仍然是一个高度可取的目标，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希望的方法。将嵌合抗原受体（CAR）的引入T细胞引入了几乎任何表面分子特有的效应细胞的快速生成，并显着提高了肿瘤特异性CTL的过继转移的临床适用性。我们的中心假设是，将ASCT与肿瘤定向的CAR+ T细胞相结合，应该可以保留自体SCT的出色安全性，同时添加有效的GVT分量。我们建议在患有ASCT和高复发风险的CD30+恶性肿瘤（包括HL和ALCL）的患者中检验这一假设，因为我们有一种针对CD30分子的新型汽车，并敦促采用新的基于免疫的方法，以防止这些患者的ASCT疾病复发。在拟议的第一阶段研究中，如果将基于CAR的疗法与ASCT相结合将降低与高肿瘤负担相关的毒性风险，肿瘤免疫逃避这种细胞疗法的风险，以及如果与我们的新型汽车接枝并在IL-15中交接的T细胞将增强持久性，膨胀，扩张和体内活性。这项人类研究完成后，我们将知道CAR+ T细胞的输注是否安全，以及细胞是否持续并且具有体内功能。所有执行研究的组件都已到位，我们拥有足够的个人和机构经验，可以确保按计划开放，完成和分析研究，从而提供有关SCT后使用T细胞免疫疗法的有价值的信息。