Project 3: Increasing the potency and accessibility of EBVSTs for the treatment of Lymphoma

项目 3：提高 EBVST 治疗淋巴瘤的效力和可及性

基本信息

批准号：
10495079
负责人：
CLIONA M ROONEY
金额：
$ 31.15万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/10495079
关键词：
Aftercare Allogenic Antigen Targeting Antigens Apoptotic Autologous B-Cell Neoplasm B-Lymphocytes BCL2 gene Bar Codes Biological Assay Blood Caspase Cell Therapy Cells Clinical Clinical Research Clinical Trials Coculture Techniques Cytokine Receptors Cytokine Signaling Data Donor Selection Dose EBV specific T-cells Effector Cell Environment Epstein-Barr Virus latency Frequencies Functional disorder Funding Gene Expression Goals Graft Rejection HDAC4 gene Histone Deacetylase Inhibitor Human Human Herpesvirus 4 IL7 Signaling Pathway Immune response In Vitro In complete remission Infusion procedures Interleukin 7 Receptor Link Lymphoma Lytic Phase Malignant - descriptor Measures Modeling Mus Neuroblastoma Patients Peripheral Blood Mononuclear Cell Phenotype Pre-Clinical Model Predisposition Proliferating Resistance Saliva Signal Transduction Specificity Stat5 protein Stem cell transplant T cell anergy T cell therapy T-Lymphocyte T-Lymphocyte Subsets TNFRSF8 gene Testing Time Toxic effect Transgenes Treatment Failure Viral Antigens Viral load measurement Virus Virus Replication Xenograft Model anergy arm cancer therapy cell killing chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy cytokine release syndrome cytotoxic effector T cell graft vs host disease humanized mouse improved in vivo mouse model neoplastic cell novel strategies pre-clinical preclinical study prevent programs receptor expression relapse patients response transforming virus tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY / ABSTRACT The broad goal of Project 3 is to devise and implement novel strategies of effective, low-toxicity EBV-specific T cell (EBVST) therapy for EBV-positive lymphomas; approximately 30% of all human lymphomas. The lymphoma environment lacks the positive signaling required to maintain the anti-tumor activities of EBVSTs and instead expresses inhibitory signals producing EBVST anergy. Our constitutive interleukin 7 receptor (C7R) not only provides intrinsic cytokine signaling but activates an anti-apoptotic program that provides resistance to tumor induced T-cell dysfunction. C7R produced expansion of GD2.CAR T-cells that was similar to lymphodepleting chemotherapy (LD) in patients with neuroblastoma, and unlike LD, did not induce cytokine release syndrome (CRS). C7R expression in EBVSTs produced more rapid clearance of autologous EBV-transformed B-cell tumors in an NSG xenograft model and in Aim 1, we will test the hypothesis that C7R will enhance the expansion and persistence of EBVSTs in patients with lymphoma, will provide resistance to the immunosuppressive tumor microenvironment and provide a non-toxic alternative to LD. EBV-reactivation produces exponential expansion of infused autologous EBVSTs and tumor clearance in patients with EBV+ lymphoma. In Aim 2 we will clinically evaluate an EBV latency reversal agent, panobinostat (PBST) to enhance the expansion and function of C7R-EBVSTs. PBST also has direct anti-lymphoma activity by downregulating STAT5 and increasing the expression of pro-apoptotic caspases. These inhibitory activities will be counteracted in EBVSTs by the C7R that upregulates STAT5. Thus, our second hypothesis (Aim 2) is that PBST will simultaneously increase antigen stimulation of C7R-EBVST while selectively increasing susceptibility of the tumor cells to C7R-EBVST killing. The ideal therapy for EBV+ lymphoma would be off-the-shelf, partially-HLA matched C7R-EBVSTs that are potent, immediately available, and relatively inexpensive. However, graft versus host disease (GVHD) and graft rejection caused by alloreactive T-cells curtail the clinical efficacy of allogeneic cell therapies. Aim 3 will evaluate CD30.CAR-modified C7R-EBVSTs to resolve both problems, EBVSTs have not produced GVHD in hundreds of allogeneic recipients in the stem cell transplant setting, and since alloactivated T-cells upregulate CD30, they should be eliminated by the CD30.CAR. Indeed banked CD30.CAR-EBVSTs have safely produced clinical responses (3 complete), in 6 of 8 patients with CD30+lymphoma. However, CD30.CAR-EBVSTs did not persist. Hence Aim 3 will test the hypothesis that C7R will enhance CD30.CAR-EBVST persistence and anti-tumor activity in a murine allo-rejection model. These 3 hypotheses will be tested in the three specific Aims: Aim 1. Can C7R enhance expansion, and long-term activity of EBVSTs in patients with EBV+ lymphoma? Aim 2. Can panobinostat boost EBVST expansion and anti-tumor activity in patients? Aim 3. Can CD30.CAR prevent rejection of C7R-EBVSTs in a murine allo-rejection model?

项目概要/摘要项目 3 的总体目标是设计和实施有效、低毒性的 EBV 特异性 T 的新策略 EBV 阳性淋巴瘤的细胞（EBVST）疗法；约占所有人类淋巴瘤的 30%。淋巴瘤环境缺乏维持 EBVST 抗肿瘤活性所需的正向信号传导，而是表达产生 EBVST 无反应性的抑制信号。我们的组成型白细胞介素 7 受体 (C7R) 不仅提供内在的细胞因子信号传导，但激活抗凋亡程序，从而提供对肿瘤的抵抗力诱导T细胞功能障碍。 C7R 产生类似于淋巴细胞清除的 GD2.CAR T 细胞扩增神经母细胞瘤患者的化疗（LD）与 LD 不同，不会诱发细胞因子释放综合征（CRS）。 EBVST 中的 C7R 表达使自体 EBV 转化的 B 细胞的清除速度更快在 NSG 异种移植模型和目标 1 中，我们将测试 C7R 会增强肿瘤淋巴瘤患者中 EBVST 的扩展和持续存在，将为免疫抑制肿瘤微环境，并提供 LD 的无毒替代品。 EBV 重新激活使输注的自体 EBVST 呈指数扩张，并清除肿瘤 EBV+淋巴瘤患者。在目标 2 中，我们将临床评估 EBV 潜伏期逆转剂帕比司他 (PBST) 增强 C7R-EBVST 的扩展和功能。 PBST 还具有直接抗淋巴瘤活性通过下调 STAT5 并增加促凋亡 caspase 的表达。这些抑制活性在 EBVST 中将被上调 STAT5 的 C7R 抵消。因此，我们的第二个假设（目标 2）是 PBST 将同时增加 C7R-EBVST 的抗原刺激，同时选择性地增加肿瘤细胞对 C7R-EBVST 杀伤的敏感性。 EBV+ 淋巴瘤的理想疗法是现成的、部分 HLA 匹配的 C7R-EBVST 有效、立即可用且相对便宜。然而，移植物抗宿主病（GVHD）和移植物同种异体反应性 T 细胞引起的排斥反应降低了同种异体细胞疗法的临床疗效。目标 3 将评估 CD30.CAR修饰的C7R-EBVSTs解决了这两个问题，EBVSTs在数百年中没有产生GVHD 干细胞移植环境中的同种异体受者，由于同种异体激活的 T 细胞上调 CD30，他们应被 CD30.CAR 消除。事实上，库存的 CD30.CAR-EBVST 已安全生产出临床 8 名 CD30+ 淋巴瘤患者中有 6 名有缓解（3 名已完成）。然而，CD30.CAR-EBVST 并没有持续存在。因此目标3将检验C7R将增强CD30.CAR-EBVST持久性和抗肿瘤作用的假设小鼠同种异体排斥模型中的活性。这 3 个假设将在三个具体目标中得到检验：目标 1. C7R 能否增强 EBV+ 淋巴瘤患者 EBVST 的扩增和长期活性？目标 2. 帕比司他能否增强患者的 EBVST 扩增和抗肿瘤活性？目标 3. CD30.CAR 能否防止小鼠同种异体排斥模型中 C7R-EBVST 的排斥？