Mechanisms of treatment failure in chimeric antigen receptor T cell therapy

嵌合抗原受体T细胞治疗失败的机制

基本信息

批准号：
10640839
负责人：
Brian Till
金额：
$ 48.95万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640839
关键词：
Activities of Daily Living Acute Lymphocytic Leukemia Adjuvant Therapy Adoptive Immunotherapy Aftercare Antigen Targeting Antitumor Response Area Autologous B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell NonHodgkins Lymphoma Biologic Characteristic Biological Biological Process Biopsy Blood Component Removal Blood specimen CAR T cell therapy CD19 gene CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular biology Characteristics Chronic Chronic Lymphocytic Leukemia Clinical Clinical Trials Color Correlative Study Counseling Data Data Analyses Dedications Disease Disease remission Exposure to Flow Cytometry Frequencies Funding Future Gene Expression Profile Gene Expression Profiling Generations Human Immune Immunohistochemistry Immunophenotyping Immunotherapy In complete remission Infiltration Infusion procedures Investigation Leukapheresis Ligands Lymphoma Lymphoma cell MS4A1 gene Malignant lymphoid neoplasm Methodology Methods Multi-Institutional Clinical Trial Mus Non-Hodgkin&apos s Lymphoma Patient Selection Patients Phase I/II Clinical Trial Phenotype Predisposition Process Production Prognosis Protein Secretion Publishing Recurrence Refractory Refractory Disease Relapse Research Design Research Personnel Resistance Sampling Secure Small-Cell Lymphoma Source Specimen T cell differentiation T cell therapy T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Time Treatment Failure Tumor Escape Tumor Promotion Tumor-infiltrating immune cells Work chimeric antigen receptor chimeric antigen receptor T cells combinatorial design effective therapy effector T cell exhaustion experimental study immunogenic improved in vivo insight manufacture manufacturing cost manufacturing technology multidimensional data neoplastic cell non-Hodgkin&apos s lymphoma patients partial response participant enrollment peripheral blood pre-clinical predict responsiveness recruit responders and non-responders response single-cell RNA sequencing spatial relationship standard care theories therapy resistant treatment response tumor tumor immunology tumor microenvironment tumor-immune system interactions vector

项目摘要

PROJECT SUMMARY / ABSTRACT Adoptive immunotherapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is highly promising for B-cell malignancies. However, fewer than half of patients with relapsed non-Hodgkin lymphoma (NHL) achieve durable remissions following treatment with CD19-targeted CAR T cells. In some cases this results from target antigen loss or rejection of the infused cells due to immunogenic murine CAR components, but in most cases the causes of treatment resistance or relapse after an initial response remain poorly understood. We propose a plan to elucidate the reasons for treatment failure in a recently initiated CAR T cell clinical trial by carefully evaluating biological features of the tumor and tumor microenvironment before and after CAR T cell therapy as well as phenotypes of patient T cells and infused CAR T cells. As part of our phase I/II clinical trial of a fully human 3rd generation CD20-specific CAR in patients with relapsed or refractory B-cell NHL (funded by a separate source), all patients undergo mandatory tumor biopsies before and after treatment. This will allow us to discover biological characteristics predictive of responsiveness to treatment, and to evaluate adaptive changes in the tumor over time to reveal the mechanisms of immune escape leading to relapse. We will employ a step-wise approach using state-of- the-art methodologies, including multicolor flow cytometry, single-cell RNA sequencing and gene expression profiling, and multiplex immunohistochemistry. We have assembled a world class team of investigators that will evaluate the potential obstacles to successful therapy, including tumor entry barriers, tumor infiltration by suppressive cells, CAR T-cell exposure to inhibitory ligands or secreted proteins, and CAR T-cell exhaustion. There is a robust body of preclinical data demonstrating that less-differentiated T cell subsets impart superior in vivo expansion, persistence, and anti-tumor efficacy, compared with more differentiated T cell subsets. Recent data from a small trial suggests that the frequency of these less-differentiated CD8+ cell subsets before and after CAR T cell manufacturing correlates with clinical responses in patients with chronic lymphocytic lymphoma receiving CD19-targeted CAR T cells. These results have important implications, but must be validated in other settings. We will quantify less-differentiated T cell subtypes prior to leukapheresis, as well as in the infused CAR T cell products, and correlate these characteristics with anti-tumor responses and in vivo expansion and persistence. We anticipate that these correlative studies will yield critical insights into the reasons why CAR T cell therapy is successful for some NHL patients but not others. We are hopeful that our findings will help to guide patient selection and counseling, and inform future strategies to overcome these obstacles through improved cell manufacturing technologies, CAR vector design, and/or combinatorial adjuvant therapies, not only for CD20-specific CAR T cells, but also for CAR T cell therapy for other targets.

项目概要/摘要使用表达嵌合抗原受体 (CAR) 的转基因 T 细胞进行过继免疫治疗对于 B 细胞恶性肿瘤很有希望。然而，只有不到一半的非霍奇金复发患者淋巴瘤 (NHL) 在使用 CD19 靶向 CAR T 细胞治疗后实现持久缓解。在一些这种情况是由于免疫原性鼠 CAR 导致靶抗原丢失或输注细胞排斥所致成分，但在大多数情况下，治疗耐药或初始反应后复发的原因仍然存在不太了解。我们提出了一项计划来阐明最近启动的 CAR 治疗失败的原因 T细胞临床试验之前仔细评估肿瘤的生物学特征和肿瘤微环境 CAR T 细胞治疗后以及患者 T 细胞和输注 CAR T 细胞的表型。作为我们针对患有以下疾病的患者进行全人第三代 CD20 特异性 CAR 的 I/II 期临床试验的一部分复发或难治性 B 细胞 NHL（由单独来源资助），所有患者均接受强制性肿瘤治疗治疗前和治疗后进行活检。这将使我们能够发现预测的生物学特征对治疗的反应，并评估肿瘤随时间的适应性变化，以揭示导致复发的免疫逃逸机制。我们将采用逐步的方法，使用状态最先进的方法，包括多色流式细胞术、单细胞 RNA 测序和基因表达分析和多重免疫组织化学。我们组建了一支世界一流的调查团队评估成功治疗的潜在障碍，包括肿瘤进入障碍、肿瘤浸润抑制性细胞、CAR T 细胞暴露于抑制性配体或分泌蛋白以及 CAR T 细胞耗竭。大量临床前数据表明，分化程度较低的 T 细胞亚群可赋予与分化程度更高的 T 细胞相比，具有优越的体内扩增、持久性和抗肿瘤功效子集。一项小型试验的最新数据表明，这些分化程度较低的 CD8+ 细胞的频率 CAR T 细胞制造前后的子集与慢性病患者的临床反应相关接受 CD19 靶向 CAR T 细胞治疗的淋巴细胞淋巴瘤。这些结果具有重要意义，但是必须在其他设置中进行验证。我们将在白细胞分离术之前量化低分化 T 细胞亚型，以及输注的 CAR T 细胞产品中，并将这些特征与抗肿瘤反应相关联以及体内的扩展和持久性。我们预计这些相关研究将对 CAR T 细胞的原因产生重要的见解。治疗对某些 NHL 患者有效，但对其他患者则不然。我们希望我们的发现能够帮助指导患者选择和咨询，并为未来的策略提供信息，通过改进克服这些障碍细胞制造技术、CAR 载体设计和/或组合辅助疗法，不仅用于 CD20特异性CAR T细胞，也可用于其他靶点的CAR T细胞治疗。