Engineered CD4 Tregs Targeting B-ALL and AML

针对 B-ALL 和 AML 的工程化 CD4 Tregs

• 批准号: 10554605
• 负责人: John E. Wagner
• 金额: $ 35.08万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554605
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Address; Adverse effects; Allogenic; Antibodies; Antigens; Autologous; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; CAR T cell therapy; CD19 gene; CD8B1 gene; Cell Therapy; Cells; Characteristics; Clinical Trials; Complement; Data; Development; Dose; Drug Kinetics; Economics; Effectiveness; Effector Cell; Engineering; FDA approved; Failure; Funding; Future; Genetic Engineering; Geography; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Immune; Immunologic Receptors; In Vitro; Industrialization; Inflammatory; Interleukin 2 Receptor; Interleukin-2; Logistics; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Myelogenous; Neurotoxicity Syndromes; Organ; Patients; Persons; Pharmaceutical Preparations; Phase; Phase I/II Trial; Pre-Clinical Model; Prevention trial; Production; Proliferating; Refractory; Regulatory T-Lymphocyte; Relapse; Resistance; Risk; Safety; Salvage Therapy; Signal Transduction; Solid; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Tumor Antigens; acute myeloid leukemia cell; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; chronic inflammatory disease; cytokine; cytokine release syndrome; cytotoxicity; exhaustion; first-in-human; graft vs host disease; improved; in vivo; large scale production; manufacture; nanobodies; novel strategies; peripheral tolerance; potency testing; pre-clinical; prevent; progenitor; public health relevance; research clinical testing; safety testing; side effect; tumor

PROJECT SUMMARY/ABSTRACT Chimeric antigen receptor (CAR)-T cell therapies have dramatically shifted the treatment paradigm for many patients with cancer. Broader use of autologous CAR-T cell therapies, however, is hindered by complicated logistics, variable quality, T cell exhaustion, antigen escape and on-target/off-tumor effects and other toxicities, like CRS. The broad objective is to address these issues by the development of a safe and effective off-the- shelf cell therapy. To accomplish this, we propose a different cellular vehicle, specifically Regulatory T Cells (Tregs). Advantages of Tregs include (a) an inherent ability to suppress the release of proinflammatory cytokines and host mediated allogeneic rejection, and (b) proliferative capacity for large-scale expansion and genetic engineering, ideal characteristics of an allogeneic immune effector cell (IEC) therapeutic. Based on the safety and efficacy profile of third party Tregs previously tested in phase I/II trials for prevention of graft-versus- host disease (GVHD), and their tumoricidal potency in preclinical models, this strategy addresses some of the grand challenges facing allogeneic IECs. During the current funding period, in proof of concept studies, we demonstrated the tumoricidal activity of Treg expressing CARs targeting CD19+ and CD83+ hematological malignancies. Our central hypothesis is that allogeneic Tregs can be engineered for enhanced persistence and maximal tumor killing with reduced risks of adverse side effects compared to conventional T cells. Specifically, we will establish the safety profile of CAR19 Tregs at the maximal tolerable dose without and with rhIL-2 in patients with relapsed/refractory CD19+ acute lymphocytic leukemia (Aim 1A, Aim 1B), assessing in vivo pharmacokinetics and persistence as well as tumoricidal activity. To avoid the potential side effects of systemic rhIL-2 and avoid bystander activation, we will engineer CAR19 Tregs to express an orthoIL2Rβ responsive to orthoIL-2 to maximize persistence and tumor killing (Aim 1C). In Aim 2, we will test the potency of nanoCAR Tregs targeting CD83 on AML cells and not myeloid progenitors (Aim 2A). Additionally, to minimize Treg exhaustion from tonic stimulation as well as enhance safety, Tregs will be engineered with a drug inducible CAR permitting control over its activation (Aim 2B). These IND enabling studies will support future clinical testing. IMPACT. The availability of safer and more effective allogeneic ‘off-the-shelf’ tTreg IECs would address a critical unmet need, overcoming some of the principal limitations of individualized products. 1

项目摘要/摘要 嵌合抗原受体（CAR）-T细胞疗法已急剧改变了许多人的治疗范例 癌症患者。然而，更广泛的自体CAR-T细胞疗法的使用受到复杂的阻碍 物流，可变质量，T细胞耗尽，抗原逃逸和靶向/肿瘤效应和其他毒性， 像CRS。广泛的目标是通过开发安全有效的现场来解决这些问题 货架细胞疗法。为此，我们提出了另一种细胞媒介物，特别是调节T细胞 （Tregs）。 Treg的优点包括（a）抑制促炎性释放的遗传性 细胞因子和宿主介导的同种异体排斥反应，（b）大规模扩张和 基因工程，同种异体免疫效应细胞（IEC）疗法的理想特征。基于 先前在I/II阶段试验中测试的第三方Treg的安全性和有效性，以预防移植物 - 宿主病（GVHD）及其在临床前模型中的结核效力，该策略解决了一些 同种异体IEC面临的巨大挑战。在当前的资金期间，在概念研究证明中，我们 证明了靶向CD19+和CD83+血液学的Treg表达的Treg活性 恶性肿瘤。我们的中心假设是可以设计同种异体Treg，以增强持久性 与常规T细胞相比，最大的肿瘤杀死，副作用的风险降低。 具体而言，我们将在最大可耐受剂量的情况下建立CAR19 Treg的安全性 继电器/难治性CD19+急性淋巴细胞性白血病患者的RHIL-2（AIM 1A，AIM 1B），评估 体内药代动力学和持久性以及结核活动。为了避免潜在的副作用 全身性RHIL-2并避免旁观者激活，我们将设计Car19 Tregs以表达Orthoil2Rβ 对Orthoil-2响应，以最大化持久性和肿瘤杀伤（AIM 1C）。在AIM 2中，我们将测试效力 靶向CD83在AML细胞而不是髓样祖细胞上的纳米Treg（AIM 2A）。此外， 最大程度地减少滋补刺激和增强安全性的筋疲力尽，Tregs将通过 药物可诱导的汽车允许控制其激活（AIM 2B）。这些促成研究将支持 未来的临床测试。影响。更安全，更有效的同种异体“现成” ttreg IEC的可用性 将解决一个关键的未满足需求，克服了个性化产品的一些主要局限性。 1