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：
9323482
负责人：
Barbara Savoldo
金额：
$ 44.71万
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 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9323482
关键词：
Address Adjuvant Therapy Adoptive Transfer Aftercare Allografting Antibodies Antigen Targeting Antigens Autologous Autologous Stem Cell Transplantation Avidity Binding Biological Bulky Disease CD30 Antigens Cell Line Cell Therapy Cell physiology Cells Clinical Cultured Cells Cytotoxic T-Lymphocytes Development Disease Documentation Effector Cell Ensure Environment Generations Graft-Versus-Tumor Induction Hematologic Neoplasms Hodgkin Disease Immune Immune Evasion 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 Immunologic Specificity T-Lymphocyte TNFRSF8 gene Testing Toxic effect Transplantation Treatment Failure Tumor Antigens Tumor Burden Tumor Lysis Syndrome arm base burden of illness chimeric antigen receptor clinical application cytokine cytotoxic density experience high risk in vivo man neoplastic cell novel outcome forecast phase 1 study prevent public health relevance receptor reconstitution relapse risk risk minimization success tumor tumor microenvironment virtual

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）：干细胞移植经常被用作许多预后不良的血液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，因为缺乏由同种异体移植物输注的供体来源的免疫成分介导的移植物抗肿瘤 (GVT) 效应。因此，移植后开发无毒的“巩固治疗”仍然是一个非常理想的目标，而抗原/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途的方法。将嵌合抗原受体 (CAR) 引入 T 细胞可以快速生成对几乎任何表面分子具有特异性的效应细胞，并显着提高了肿瘤特异性 CTL 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 CAR+ T 细胞相结合，应该可以保留自体 SCT 的卓越安全性，同时添加有效的 GVT 成分。我们建议在接受 ASCT 且复发风险高的 CD30+ 恶性肿瘤（包括 HL 和 ALCL）患者中检验这一假设，因为我们有一种针对 CD30 分子的新型 CAR，并且迫切需要新的基于免疫的方法来预防疾病复发。这些患者进行 ASCT。在拟议的 I 期研究中，我们将讨论基于 CAR 的疗法与 ASCT 相结合是否会降低与高肿瘤负荷相关的毒性风险、该细胞疗法的肿瘤免疫逃避，以及是否移植了我们的新型 CAR 的 T 细胞并在 IL 中扩展-15将具有增强的持久性、扩展性和体内活性。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。执行该研究的所有组成部分均已到位，我们拥有足够的个人和机构经验，以确保该研究按计划开放、完成和分析，提供有关 SCT 后使用 T 细胞免疫疗法的宝贵信息。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15.

使用优化的 GD2 特异性嵌合抗原受体和 Interleukin-15 重定向 T 细胞来根除神经母细胞瘤。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Chen, Yuhui;Sun, Chuang;Landoni, Elisa;Metelitsa, Leonid;Dotti, Gianpietro;Savoldo, Barbara
通讯作者：
Savoldo, Barbara

Treating hematological malignancies with cell therapy: where are we now?

用细胞疗法治疗血液恶性肿瘤：我们现在在哪里？

DOI：
发表时间：
2018-01
期刊：
影响因子：
4.6
作者：
Landoni, Elisa;Savoldo, Barbara
通讯作者：
Savoldo, Barbara

Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies.

利用基于细胞的疗法来克服血液恶性肿瘤中的免疫逃避。

DOI：
发表时间：
2016
期刊：
影响因子：
20.3
作者：
Sun, Chuang;Dotti, Gianpietro;Savoldo, Barbara
通讯作者：
Savoldo, Barbara

Patient-reported outcomes in CD30-directed CAR-T cells against relapsed/refractory CD30+ lymphomas.

患者报告的 CD30 定向 CAR-T 细胞治疗复发/难治性 CD30 淋巴瘤的结果。

DOI：
发表时间：
2023-08
期刊：
影响因子：
0
作者：
Tschernia, Nicholas P;Heiling, Hillary;Deal, Allison M;Cheng, Catherine;Babinec, Caroline;Gonzalez, Megan;Morrison, J Kaitlin;Dittus, Christopher;Dotti, Gianpietro;Beaven, Anne W;Serody, Jonathan S;Wood, William A;Savoldo, Barbara;Grover, Nat
通讯作者：
Grover, Nat

Targeting Immune System Alterations in Hodgkin Lymphoma.

针对霍奇金淋巴瘤的免疫系统改变。