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

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

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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

项目摘要尽管发展了基于CD30抗体的疗法并使用检查点抑制剂CD30+ 恶性肿瘤仍然难以消除，其中大部分患者发生复发。这 T细胞中嵌合抗原受体（CAR）的工程推动了肿瘤特异性的快速产生细胞，增加了采用转移细胞疗法的临床适用性。我们已经发展了免疫基于基于用汽车重定向的T细胞靶向CD30抗原的疗法，并在I/II期中显示试验，他们在复发/难治（R/R）霍奇金淋巴瘤（HL）患者中的收养转移是安全的产生抗肿瘤活性，包括完整的反应。现在，我们建议进一步提高患者完全反应的反应率和长期耐用性通过克服基于CD30的主要障碍CD30+恶性肿瘤。我们将对包括HL和皮肤T细胞在内的R/R CD30+恶性肿瘤患者进行I期临床试验淋巴瘤（CTCL），T细胞设计以共表达CD30.CAR和特定的趋化因子受体 CCR4，以证明增强的迁移和对肿瘤的运输进一步改善了抗肿瘤活性。然后，我们将监测（在肿瘤微环境中，在系统和本地）免疫功能和 CD30+恶性肿瘤患者接受CAR T细胞的曲目，以识别我们的优势和限制提出理由组合疗法的方法。最后，我们计划研究这些患者的髓样细胞特征，以及它在塑造促进方面的贡献在CAR-T细胞疗法的背景下，肿瘤景观。完成研究后，我们将了解CAR-TS的定向归巢对体内功能的临床影响，对免疫功能的影响和贡献以及与这些相关的亲瘤景观的影响和贡献疗法。进行研究的所有组件都已到位，我们拥有足够的个人和机构确保研究将按计划完成和分析的经验