Project 1: Immunotherapy of B cell lymphoma with NKT cells

项目1：NKT细胞免疫治疗B细胞淋巴瘤

• 批准号: 10495077
• 负责人: Leonid S Metelitsa
• 金额: $ 31.92万
• 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: 2007-09-11 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10495077
• 关键词: Address; Adult; Affect; Allogenic; Antigen Targeting; Autologous; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; CAR T cell therapy; CD19 gene; CD2 gene; CD8B1 gene; Cancer Model; Cell Therapy; Cells; Clinical; Cytotoxic T-Lymphocytes; Development; Disease; Down-Regulation; Engineering; FDA approved; Foundations; Genetic Transcription; Goals; Graft Rejection; Guidelines; Histocompatibility Antigens Class II; Image; Immune; Immune response; Immunologics; Immunotherapy; In Vitro; In complete remission; Interleukin-15; Lymphoma; Lymphoma cell; Malignant Neoplasms; Measures; Mediating; MicroRNAs; Modeling; Molecular Analysis; Monitor; Myeloid-derived suppressor cells; National Cancer Institute; Natural Killer Cells; Neoplasms; Patients; Pharmacology; Phase I Clinical Trials; Progressive Disease; Property; Recurrence; Refractory; Regulation; Relapse; Resistance; Route; Safety; Series; Site; Source; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Trans-Activators; Transgenic Organisms; Tumor Immunity; beta-2 Microglobulin; cancer type; chimeric antigen receptor; clinical investigation; cost; cost effective; cytotoxicity; exhaustion; first-in-human; fitness; fitness test; graft vs host disease; graft vs leukemia effect; high risk; in vivo; knock-down; lymphoblast; macrophage; neoplasm immunotherapy; neoplastic cell; non-Hodgkin' s lymphoma patients; novel; overexpression; patient variability; pediatric patients; peripheral blood; pre-clinical; promoter; research clinical testing; response; small hairpin RNA; therapeutic evaluation; tumor

PROJECT SUMMARY / ABSTRACT Despite remarkable progress achieved with chimeric antigen receptor (CAR)-expressing T cells in the treatment of relapsed/refractory B lineage neoplasms, CD19-specific CAR (CAR.CD19) autologous T cell products are not curative for more than half of B-NHL patients. The long-term goal of Project 1 is to develop a safe and effective immunotherapy for B-NHL using both the natural and engineered properties of CD1d-restricted Va24-invariant natural killer T cells (NKTs). Unlike polyclonal T cells, NKTs have natural antilymphoma activity via direct cytotoxicity against CD1d+ lymphoblasts or/and by activation of other immune effectors; further, allogeneic NKTs do not produce graft-versus-host disease (GvHD) and can be prepared as “off-the-shelf” products. During the current project period, we have initiated a first-in-human phase I clinical trial of allo-CAR.CD19 NKTs (NCT03774654) and have treated the first four patients. The therapy was well tolerated and produced objective responses in three patients. However short persistence of CAR.CD19 NKTs in patient peripheral blood may decrease durability of response. To protect the therapeutic NKTs from host-mediated rejection, we have developed new CAR constructs that co-express artificial micro(mi)RNA (amiR), consisting of promoterless miRNA frames with embedded shRNA sequences targeting B2M and the class II major histocompatibility complex transactivator (CIITA). These CAR/amiR constructs produce a graded downregulation of HLA class-I and class-II in CAR-NKTs making them resistant to allogenic T and NK cells. We have also found that CAR-NKT therapeutic potency can be augmented by pharmacologic or transgenic regulation of LEF1 transcriptional activity, which controls NKT cell functional fitness. We hypothesize that allo-CAR.CD19 NKTs will continue to be well tolerated and effective against B-NHL; their therapeutic potency can be further increased via amiR-mediated protection from immune rejection and via LEF1-mediated retention of their antitumor activity. The following three specific aims will test our hypotheses: 1) to determine the safety, efficacy, and immunological activity of allo- CAR.CD19 NKTs in B-NHL patients; 2) to produce cGMP allo-NKTs co-expressing CAR.CD19 with B2M and CIITA amiRs and to determine the safety, efficacy, and immunological activity of allo-CAR.CD19/amiR NKTs in B-NHL patients; 3) to evaluate the mechanism by which LEF1 controls NKT cell functional fitness and test the therapeutic potency of NKTs co-expressing CAR.CD19 and LEF1 in pre-clinical B cell lymphoma models. The ongoing and proposed studies are the first to rigorously evaluate the utility of NKTs as a novel cellular platform for redirected “off-the-self” immunotherapy. If proven to be safe and effective, this approach will provide a foundation for a cost-effective cell therapy platform for B-NHL and perhaps other types of cancer as well.

项目总结/摘要 尽管嵌合抗原受体（CAR）表达T细胞在治疗中取得了显着进展， 在复发性/难治性B谱系肿瘤中，CD 19特异性CAR（CAR.CD19）自体T细胞产物不是 治疗超过一半的B-NHL患者。项目1的长期目标是开发一种安全有效的 使用CD 1d限制性Va 24-不变量的天然和工程特性的B-NHL免疫疗法 自然杀伤T细胞（NKT）。与多克隆T细胞不同，NKT具有天然的抗淋巴瘤活性，通过直接免疫抑制。 针对CD 1d+淋巴母细胞的细胞毒性或/和通过激活其他免疫效应物;此外，同种异体NKT 不产生移植物抗宿主病（GvHD），并且可以制备成“现成”产品。期间 在当前项目期间，我们已经启动了allo-CAR. CD 19 NKT的首次人体I期临床试验 （NCT 03774654），并治疗了前四名患者。该疗法耐受性良好， 三个病人的反应。然而，CAR.CD19 NKT在患者外周血中的短暂持续性可能 降低反应的持久性。为了保护治疗性NKT免受宿主介导的排斥反应，我们 开发了新的CAR构建体，共表达人工微（mi）RNA（amiR），由无启动子的 具有靶向B2 M和II类主要组织相容性的嵌入式shRNA序列的miRNA框架 复合物反式激活因子（CIITA）。这些CAR/amiR构建体产生HLA I类的分级下调， 和CAR-NKT中的II类，使其对同种异体T和NK细胞具有抗性。我们还发现CAR-NKT 治疗效力可以通过LEF 1转录活性的药理学或转基因调节来增强， 它控制着NKT细胞的功能适应性。我们假设allo-CAR. CD 19 NKT将继续良好地表达， 耐受且有效对抗B-NHL;它们的治疗效力可通过amiR介导的 保护免受免疫排斥和通过LEF 1介导的保留其抗肿瘤活性。以下三 具体的目的将测试我们的假设：1）确定的安全性，有效性，和免疫活性的allo- CD 19 NKT; 2）产生共表达CAR. 在CIITA amiR中测定allo-CAR. CD 19/amiR NKT的安全性、有效性和免疫活性， B-NHL患者; 3）评估LEF 1控制NKT细胞功能适应性的机制，并测试LEF 1对NKT细胞功能适应性的影响。 共表达CAR. CD 19和LEF 1的NKT在临床前B细胞淋巴瘤模型中的治疗效力。的 正在进行的和拟议中的研究是第一个严格评估NKT作为一种新型细胞平台的效用的研究 用于重定向的“脱离自我”免疫疗法。如果被证明是安全和有效的，这种方法将提供一个 为B-NHL和其他类型的癌症提供具有成本效益的细胞治疗平台。