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

• 批准号: 10704650
• 负责人: CLIONA M ROONEY
• 金额: $ 31.14万
• 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/10704650
• 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; Engraftment; Environment; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Lymphoma; 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; Sorting; 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; Xenograft Model; anergy; arm; cancer therapy; cell killing; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical efficacy; constitutive expression; cytokine release syndrome; cytotoxic; effector T cell; graft vs host disease; humanized mouse; improved; in vivo; inflammatory milieu; manufacture; 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

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?

项目摘要 /摘要 项目3的广泛目标是设计和实施有效，低毒性EBV特异性T的新颖策略 EBV阳性淋巴瘤的细胞（EBVST）治疗；大约30％的人类淋巴瘤。淋巴瘤 环境缺乏维持EBVST的反肿瘤活动所需的积极信号，而是 表达产生EBVST ANERGY的抑制信号。我们的本构白介素7受体（C7R）不仅 提供固有的细胞因子信号传导，但激活了抗凋亡程序，该程序可为肿瘤提供抗性 诱导的T细胞功能障碍。 C7R产生的GD22。CART细胞的扩展类似于淋巴结螺旋 与LD不同的神经母细胞瘤患者的化学疗法（LD）没有诱导细胞因子释放综合征 （CRS）。 EBVST中的C7R表达产生了自体EBV转换B细胞的更快清除 NSG异种移植模型中的肿瘤，在AIM 1中，我们将测试C7R将增强C7R的假设 EBVST在淋巴瘤患者中的扩张和持久性将对 免疫抑制性肿瘤微环境，并为LD提供无毒的替代品。 EBV反射活化产生注入自体EBVST和肿瘤清除的指数扩展 EBV+淋巴瘤患者。在AIM 2中，我们将在临床上评估EBV潜伏期逆转剂Panobinostat （PBST）增强C7R-EBVST的扩展和功能。 PBST还具有直接的抗淋巴瘤活性 通过下调STAT5并增加促凋亡胱天蛋白酶的表达。这些抑制作用 C7R将在EBVST中取消上调STAT5。因此，我们的第二个假设（AIM 2）是 PBST同时增加C7R-EBVST的抗原刺激，同时选择性增加 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是 有效，立即可用且相对便宜。但是，移植物与宿主疾病（GVHD）和移植物 同种反应性T细胞引起的排斥降低了同种异体细胞疗法的临床功效。 AIM 3将评估 CD30.CAR修饰的C7R-EBVST可以解决这两个问题，EBVST尚未在数百个中产生GVHD 干细胞移植设置中的同种异体受体，并且由于同种活化的T细胞上调CD30，因此 应由CD30.CAR消除。确实，银行CD30.CAR-EBVST安全生产了临床 在8例CD30+淋巴瘤患者中，有6例反应（3个完整）。但是，CD30.CAR-EBVST并未持续存在。 因此，AIM 3将测试C7R将增强CD30的假设。CAR-EBVST持久性和抗肿瘤 在鼠类异源反应模型中的活性。这三个假设将在三个具体目标中进行检验： AIM 1。C7R可以增强EBV+淋巴瘤患者EBVST的扩张和长期活性吗？ AIM 2。PANOBINOSTAT可以提高患者的EBVST扩展和抗肿瘤活性吗？ 目标3。CD30.CAR是否可以防止在鼠类异源反应模型中排斥C7R-EBVST？