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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