Tailoring CAR T cell therapy for Hodgkin Lymphoma

霍奇金淋巴瘤的定制 CAR T 细胞疗法

基本信息

批准号：
10626890
负责人：
Barbara Savoldo
金额：
$ 61.95万
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626890
关键词：
Acute Lymphocytic Leukemia Adoptive Cell Transfers Adoptive Transfer Affect Antibodies Antibody Therapy Antigens Antitumor Response Autologous B lymphoid malignancy Blood CAR T cell therapy CC chemokine receptor 4 CCL17 gene CD19 gene CD30 Antigens Cell Death Cell Therapy Cells Cellular immunotherapy Circulation Clinical Clinical Research Clonal Evolution Combined Modality Therapy Cross Presentation Cutaneous T-cell lymphoma Cytotoxic T-Lymphocytes Development Diffuse Large-Cell Lymphoma Disease Disease model Dose Engineering Enrollment Ensure Epitope spreading Evaluation Future Generations Hodgkin Disease Homing Human Immune Immune checkpoint inhibitor Immune response Immunomodulators Immunosuppression Immunotherapy Impairment In complete remission Incidence Individual Infiltration Inflammatory Infusion procedures Institution Lymphocyte Function Lymphoid Cell Lymphoma Macrophage Malignant Neoplasms Measures Mediating Monitor Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nature Non-Hodgkin&apos s Lymphoma Patient-Focused Outcomes Patients Phase Phase I Clinical Trials Phase I/II Trial Pre-Clinical Model Production Reed-Sternberg Cells Refractory Relapse Retroviral Vector Role Shapes Site T cell therapy T-Cell Lymphoma T-Lymphocyte T-cell receptor repertoire TNFRSF8 gene Testing Toxic effect Treatment Failure antitumor effect cancer cell chemokine chemokine receptor chimeric antigen receptor chimeric antigen receptor T cells clinical application clinical practice cytokine release syndrome effector T cell engineered T cells experience fludarabine immune function improved improved outcome in vivo inflammatory milieu manufacture migration negative affect overexpression receptor recruit response success synergism trafficking tumor tumor microenvironment tumorigenic virtual

项目摘要

PROJECT ABSTRACT Despite the development of anti-CD30 antibody-based therapies and use of checkpoint inhibitors, CD30+ malignancies remain difficult to eradicate, with relapses occurring in a significant proportion of patients. The engineering of chimeric antigen receptors (CARs) in T cells has propelled the rapid generation of tumor specific cells, increasing the clinical applicability of adoptively-transferred-cell therapies. We have developed immune based therapies based on T cells redirected with a CAR to target the CD30 antigen, and shown in a phase I/II trial that their adoptive transfer in patients with relapsed/refractory (r/r) Hodgkin's Lymphoma (HL) is safe and produces antitumor activity, including complete responses. We now propose to further increase the response rate and long-term durability of complete responses in patients with CD30+ malignancies by overcoming a major barrier of CD30.CAR T cell based approaches. We will conduct a phase I clinical trial in patients with r/r CD30+ malignancies including HL and cutaneous T cells lymphomas (CTCL), with T cells engineered to coexpress the CD30.CAR and the specific chemokine receptor CCR4, to demonstrate that enhanced migration and trafficking to the tumor further improves antitumor activity. We will then monitor (both systemically and locally, in the tumor microenvironment) immune functions and repertoire in patients with CD30+ malignancies receiving CAR T cells, to identify strengths and limits of our approach for proposing rationale combination therapies. Finally, we plan to study the myeloid cells signatures in these patients and how it contributes in shaping the pro- tumorigenic landscape in the context of CAR-T cell therapies. On completion of our study we will know the clinical impact of directed homing of CAR-Ts on in vivo functionality, the effects and contribution on immune functions and on the pro-tumorigenic landscape associated with these therapies. All components to execute the study are in place and we have sufficient individual and institutional experience to ensure the study will be completed and analyzed as planned

项目摘要尽管开发了基于抗 CD30 抗体的疗法并使用了检查点抑制剂，但 CD30+ 恶性肿瘤仍然难以根除，很大一部分患者会出现复发。这 T 细胞中的嵌合抗原受体 (CAR) 工程推动了肿瘤特异性抗体的快速生成细胞，增加了过继转移细胞疗法的临床适用性。我们已经发展出免疫力基于通过 CAR 重定向 T 细胞以靶向 CD30 抗原的疗法，并在 I/II 期试验中显示试验表明，它们对复发/难治性 (r/r) 霍奇金淋巴瘤 (HL) 患者的过继转移是安全且可靠的产生抗肿瘤活性，包括完全反应。我们现在建议进一步提高患者完全缓解的缓解率和长期持久性通过克服基于 CD30.CAR T 细胞的方法的主要障碍，治疗 CD30+ 恶性肿瘤。我们将对患有 r/r CD30+ 恶性肿瘤（包括 HL 和皮肤 T 细胞）的患者进行 I 期临床试验淋巴瘤 (CTCL)，T 细胞经过改造可共表达 CD30.CAR 和特定趋化因子受体 CCR4，证明增强的肿瘤迁移和运输进一步提高了抗肿瘤活性。然后，我们将监测（在肿瘤微环境中系统和局部）免疫功能和接受 CAR T 细胞治疗的 CD30+ 恶性肿瘤患者的全部方案，以确定我们的优势和局限性提出联合疗法的基本原理的方法。最后，我们计划研究这些患者的骨髓细胞特征以及它如何有助于塑造亲 CAR-T 细胞疗法背景下的致瘤景观。完成我们的研究后，我们将了解 CAR-T 定向归巢对体内功能的临床影响，对免疫功能以及与这些相关的促肿瘤景观的影响和贡献疗法。执行研究的所有组成部分均已到位，我们有足够的个人和机构确保研究按计划完成和分析的经验