Immunotherapy of B cell lymphoma with NK-T cells

NK-T 细胞对 B 细胞淋巴瘤的免疫治疗

• 批准号: 10000870
• 负责人: Leonid S Metelitsa
• 金额: $ 51.82万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000870
• 关键词: Acute Lymphocytic Leukemia; Address; Adult; Adult Non-Hodgkin' s Lymphoma; Allogenic; Antigen Targeting; Antigen-Presenting Cells; Antigens; B lymphoid malignancy; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Biological; Blast Cell; CD19 Antigens; CD19 gene; Cancer Model; Cell-Mediated Cytolysis; Cells; Childhood; Childhood Non-Hodgkin' s Lymphoma; Clinical; Clonality; Cyclic GMP; Cytotoxic T-Lymphocytes; Data; Disease; Disease remission; Engineering; Ensure; Epitopes; Evaluation; Frequencies; Funding; Future; Goals; Guidelines; Image; Immune; Immune system; Immunophenotyping; Immunotherapy; In complete remission; Leukapheresis; Lymphoid Cell; Lymphoma; Lymphoma cell; Measures; Mediating; Methods; Modeling; Molecular; Monitor; Mus; Myeloid Cells; Myeloid-derived suppressor cells; NK Cell Activation; Natural Killer Cells; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Patients; Peer Review; Phase I Clinical Trials; Phenotype; Precursor B-Lymphoblast; Property; Recurrence; Refractory; Regulation; Relapse; Reporting; Reproducibility; Route; SELL gene; Safety; Source; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Immunity; cancer cell; cancer type; chemokine; chimeric antigen receptor; chimeric antigen receptor T cells; clinical application; cytokine; cytotoxic; cytotoxicity; design; first-in-human; graft vs host disease; graft vs leukemia effect; healthy volunteer; high risk; in vivo; lymphoblast; macrophage; neoplasm immunotherapy; neoplastic cell; non-Hodgkin’s lymphoma patients; novel; pediatric patients; peripheral blood; phase I trial; preservation; response; safety and feasibility; safety testing; tumor

PROJECT SUMMARY T cells expressing CD19-specific chimeric antigen receptors (CAR.CD19) can produce high rates of complete remission among patients with refractory B-cell malignancies. However, these studies have also revealed (i) difficulties in preparing sufficient numbers of CAR-T cells from the majority of pediatric patients with non-Hodgkin lymphoma (NHL), and (ii) a growing fraction of NHL patients with delayed relapse due to inadequate persistence of CAR-T cells or loss of CD19 from tumor cells. The long-term goal of Project 4 is to develop a safe and effective immunotherapy for NHL using both the natural and engineered properties of CD1d-restricted Va24-invariant natural killer T (NKT) cells. NKTs are attractive candidates for immunotherapy. They have antilymphoma activity via direct cytotoxicity against CD1d+ lymphoblasts or by activation of other immune effectors, such as NK cells; further, allogeneic NKTs do not produce graft- versus-host disease (GvHD) and can be prepared as “off-the-shelf” products. We hypothesize that allogeneic NKTs engineered to express CAR.CD19 will show curative potential against NHL without the introduction of GvHD, a concept supported by our preliminary findings: NKTs transduced with CAR.CD19 directly kill CD19+ B lymphoblasts, can be expanded to clinical scale, and exert potent antitumor activity in xenogeneic lymphoma models. We have also shown that the CD62L+ subset of NKTs is essential for CAR.CD19-Tcell persistence and antitumor activity in vivo, and have devised means to preserve this subset of cells during CAR.CD19-NKT expansion. The following three specific aims will test our hypothesis: 1) Generate allogeneic CAR.CD19-NKTs with preserved CD62L expression and maximal antilymphoma potential, using the costimulatory aAPCs (artificial antigen-presenting cells, previously generated during the current funding period). 2) Determine the safety and antitumor activity of third-party CAR.CD19-NKTs in adult and pediatric patients with relapsed/refractory B-cell NHL. 3) Correlate the persistence, phenotype and function of CAR.CD19-NKTs with clinical responses. This study will the first in man to test the feasibility and therapeutic potential of immunotherapy with CAR-redirected NKTs. Our emphasis on CAR.CD19, with its favorable track record when expressed by T cells in NHL patients, will allow us to assess NKTs as a novel platform for NHL immunotherapy and perhaps other types of cancer as well.

项目摘要 表达CD 19特异性嵌合抗原受体（CAR.CD19）的T细胞可以产生高比率的免疫应答。 难治性B细胞恶性肿瘤患者完全缓解。然而，这些研究也 发现（i）难以从大多数儿科患者中制备足够数量的CAR-T细胞 非霍奇金淋巴瘤（NHL），和（ii）越来越多的NHL患者延迟复发，由于 CAR-T细胞的持续性不足或肿瘤细胞的CD 19丢失。项目4的长期目标是 开发一种安全有效的NHL免疫疗法，利用天然和工程特性， CD 1d限制性Va 24-不变自然杀伤T（NKT）细胞。NKT是有吸引力的候选人， 免疫疗法。它们通过对CD 1d+淋巴母细胞的直接细胞毒性或通过对CD 1d+淋巴母细胞的直接细胞毒性而具有抗淋巴瘤活性。 激活其他免疫效应物，如NK细胞;此外，同种异体NKT不产生移植物， 抗宿主病（GvHD），并且可以制备为“现成”产品。我们假设 经工程化以表达CAR.CD19的同种异体NKT将显示出针对NHL的治愈潜力，而无需 引入GvHD，这一概念得到了我们初步发现的支持：用CAR.CD19转导的NKT 直接杀死CD 19 + B淋巴母细胞，可扩大到临床规模，并在 异种淋巴瘤模型。我们还表明，NKT的CD 62 L+亚群对于 CAR.CD19-T细胞在体内的持久性和抗肿瘤活性，并已设计出保护该亚群的方法 CD 19-NKT扩增期间的细胞数量。以下三个具体目标将检验我们的假设：1） 生成具有保留的CD 62 L表达和最大抗淋巴瘤作用的同种异体CAR.CD19-NKT 潜在的，使用共刺激aAPC（人工抗原呈递细胞，先前在免疫过程中产生的）， 本期融资）。2)确定第三方CAR.CD19-NKT在 成人和儿童复发性/难治性B细胞NHL患者。3)与持久性、表型相关 和CAR.CD19-NKT的功能与临床反应。这项研究将是第一个在人类身上测试 CAR重定向NKT免疫治疗的可行性和治疗潜力。我们强调 CAR.CD19在NHL患者中由T细胞表达时具有良好的跟踪记录，将使我们能够 评估NKT作为NHL免疫治疗的新平台，也许也是其他类型的癌症。