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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：
10203890
负责人：
Barbara Savoldo
金额：
$ 63.47万
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/10203890
关键词：
Acute Lymphocytic Leukemia Adoptive Cell Transfers Adoptive Transfer Affect Antibodies Antibody Therapy Antigens Antitumor Response Autologous B lymphoid malignancy Blood Blood Circulation CAR T cell therapy CC chemokine receptor 4 CCL17 gene CD19 gene CD30 Antigens Cell Death Cell Therapy Cell physiology Cells Cellular immunotherapy 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 Lymphocyte Function Lymphoid Cell Lymphoma 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-Lymphocyte T-cell receptor repertoire TNFRSF8 gene Testing Toxic effect Treatment Failure antitumor effect base 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 macrophage 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

项目摘要尽管抗CD30抗体疗法的发展和检查点抑制剂的使用，CD30+ 恶性肿瘤仍然很难根除，相当一部分患者会复发。这个 T细胞中嵌合抗原受体(CARS)的工程已经推动了肿瘤特异性的快速产生细胞，增加过继转移细胞疗法的临床适用性。我们已经产生了免疫力基于T细胞的治疗，用CAR重定向至CD30抗原，并显示为I/II期他们在复发/难治性霍奇金淋巴瘤(HL)患者中的过继转移是安全和产生抗肿瘤活性，包括完全反应。我们现在建议进一步提高患者完全应答的应答率和长期耐受性 CD30+恶性肿瘤通过克服CD30的主要障碍。CAR T细胞为基础的方法。我们将在包括HL和皮肤T细胞在内的r/rCD30+恶性肿瘤患者中进行I期临床试验淋巴瘤(CTCL)，T细胞被设计为共表达CD30。CAR和特异性趋化因子受体 CCR4，以证明增强向肿瘤的迁移和转运进一步提高了抗肿瘤活性。然后我们将监测(系统和局部的，在肿瘤微环境中)免疫功能和 CD30+恶性肿瘤患者接受CAR T细胞的谱系，以确定我们的优势和局限性提出合理的联合疗法的方法。最后，我们计划研究这些患者的髓系细胞特征，以及它如何在形成亲骨髓细胞中起作用。 CAR-T细胞疗法背景下的致癌景观。在我们的研究完成后，我们将知道定向归巢对体内功能的临床影响，对免疫功能以及与之相关的促肿瘤环境的影响和贡献治疗。执行研究的所有组成部分都已到位，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