CAR T-Cell Therapy Targeting the Membrane-Proximal C2-Set Domain of CD33 for Treatment of Acute Myeloid Leukemia and Other CD33-Expressing Hematopoietic Neoplasms

靶向 CD33 近膜 C2 组结构域的 CAR T 细胞疗法用于治疗急性髓系白血病和其他表达 CD33 的造血肿瘤

• 批准号: 10603015
• 负责人: Roland Bruno Walter
• 金额: $ 8.95万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603015
• 关键词: CAR; Cell; Therapy; Targeting; Membrane

ABSTRACT Antigen-specific immunotherapies have long been pursued to improve outcomes in acute myeloid leukemia (AML). So far most exploited for this purpose are antibodies targeting CD33, a glycoprotein displayed on the cell surface of leukemic blasts in almost all cases and possibly leukemia stem cells in some. Improved survival of some patients treated with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this approach, but many patients with CD33+ AML do not benefit from GO. This has prompted interest in developing improved CD33-directed therapeutics, with several investigational drugs recently advancing to clinical testing. Similar to GO, all these molecules recognize immune-dominant epitope(s) within the membrane-distal V-set domain of CD33. In our preliminary studies with CD33V-set/CD3 bispecific antibodies, however, we have observed enhanced immune-effector cell function and higher cytolytic efficacy with membrane-proximal binding of CD33. We therefore hypothesize antibodies against the membrane-proximal C2-set domain will provide a superior approach to CD33-targeted immunotherapy than existing therapeutics. Moreover, since the V-set but not C2-set domain is missing in some CD33 splice variants, C2-set domain-directed antibodies can recognize all naturally- occurring variants of CD33 (i.e. are “CD33PAN antibodies”). As a first step toward our long-term goal of developing this new form of CD33 immunotherapy, we have recently generated murine and – with use of humanized (“Trianni”) mice – fully human antibodies against the C2-set domain of human CD33. Proof of concept studies with a murine CD33PAN/CD3 bispecific molecule demonstrated potent anti-leukemia activity and effective T-cell engagement. We now propose to develop a new therapy that is based on T-cells expressing chimeric antigen receptors (CARs) with human CD33PAN antibody binding sequences for patient use. We plan to rigorously test the anti-leukemia properties of these CAR T-cells in vitro and in vivo, while at the same time studying how CD33 gene-edited normal hematopoietic stem and progenitor cells (HSPCs) can mitigate toxicity of our adoptive cell therapy to normal blood cells. To accomplish these goals, we have assembled a multidisciplinary team of investigators with complementary expertise in CD33-directed immunotherapies, CAR T-cell technology, and transplantation of gene-modified HSPCs. Expected results will guide the further development of CD33PAN CAR T-cells. Alone or together with engineered hematopoietic cells to widen their therapeutic window, these cells may offer a new treatment option for AML and other CD33+ neoplasms for which outcomes continue to be unsatisfactory.

抽象的 长期以来，人们一直在寻求抗原特异性免疫疗法来改善急性髓系白血病的预后 (AML) 迄今为止，最常用于此目的的是针对 CD33 的抗体，CD33 是细胞上展示的一种糖蛋白。 几乎在所有病例中，白血病原始细胞的表面都得到改善，并且可能在某些情况下提高了白血病干细胞的存活率。 一些接受 CD33 抗体药物偶联物 gemtuzumab ozogamicin (GO) 治疗的患者验证了这一点 方法，但许多 CD33+ AML 患者并未立即从 GO 中获益，这对开发有兴趣。 改进了 CD33 导向的治疗方法，几种研究药物最近进入了临床测试。 与 GO 类似，所有这些分子都识别膜远端 V 组内的免疫显性表位 然而，在我们对 CD33V-set/CD3 双特异性抗体的初步研究中，我们观察到。 通过 CD33 的近膜结合增强免疫效应细胞功能和更高的细胞溶解功效。 因此，我们认为针对近膜 C2 组结构域的抗体将提供优越的 CD33靶向免疫疗法的方法优于现有疗法，而且，由于V-set而不是C2-set。 某些 CD33 剪接变体中缺少结构域，C2 集结构域导向的抗体可以识别所有自然- CD33 的变体（即“CD33PAN 抗体”）作为实现我们开发长期目标的第一步。 这种新形式的 CD33 免疫疗法，我们最近培育出了小鼠，并使用人源化 （“Trianni”）小鼠——针对人类 CD33 的 C2 组结构域的全人类抗体，概念验证研究。 鼠 CD33PAN/CD3 双特异性分子显示出有效的抗白血病活性和有效的 T 细胞 我们现在提议开发一种基于表达嵌合抗原的 T 细胞的新疗法。 我们计划对具有人类 CD33PAN 抗体结合序列的受体 (CAR) 进行严格测试。 研究这些 CAR T 细胞在体外和体内的抗白血病特性，同时研究 CD33 基因编辑的正常造血干细胞和祖细胞 (HSPC) 可以减轻我们的过继细胞的毒性 为了实现这些目标，我们组建了一个多学科团队。 在 CD33 定向免疫疗法、CAR T 细胞技术和 基因修饰HSPC的移植预期结果将指导CD33PAN CAR的进一步开发。 这些细胞可以单独使用或与工程造血细胞一起使用以扩大其治疗范围。 为 AML 和其他 CD33+ 肿瘤提供新的治疗选择，其结果仍然存在问题 不满意。