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.

摘要 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)。到目前为止，用于这一目的的最多是针对CD33的抗体，CD33是一种显示在细胞上的糖蛋白 几乎所有病例都有白血病原始细胞表面，部分病例可能有白血病干细胞。提高患者的存活率 一些接受CD33抗体-药物结合物getuzumab ozogamin(Go)治疗的患者证实了这一点。 方法，但许多CD33+AML患者并不受益于GO。这激起了人们对开发 改进了CD33导向的治疗方法，最近有几种研究药物进入临床测试。 与GO类似，所有这些分子都识别膜末端V-SET内的免疫优势表位(S) CD33的结构域。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 CD33的膜-近端结合增强了免疫效应细胞的功能和更高的细胞溶解效率。 因此，我们假设抗膜近端C2-SET结构域的抗体将提供更好的 CD33靶向免疫治疗的方法比现有的治疗方法更好。此外，由于V-集合而不是C2-集合 在一些CD33剪接变异体中缺失结构域，C2-SET结构域定向抗体可以识别所有自然- CD33的变异体(即“CD33PAN抗体”)。作为迈向我们发展的长期目标的第一步 这种新形式的CD33免疫疗法，我们最近产生了小鼠和-使用人源化 (“Trianni”)小鼠--针对人类CD33的C2-SET结构域的完全人类抗体。概念验证研究 小鼠CD33PAN/CD3双功能分子显示出强大的抗白血病活性和有效的T细胞 订婚。我们现在建议开发一种基于表达嵌合抗原的T细胞的新疗法 患者使用的带有人CD33PAN抗体结合序列的受体(CARS)。我们计划严格测试 研究这些CAR T细胞的体内外抗白血病特性，同时研究CD33如何 基因编辑的正常造血干细胞和祖细胞(HSPC)可以减轻过继细胞的毒性 对正常血细胞的治疗。为了实现这些目标，我们组建了一个多学科的团队， 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汽车的进一步发展 T细胞。单独或与工程造血细胞一起扩大其治疗窗口，这些细胞可能 为AML和其他CD33+肿瘤提供新的治疗选择，其疗效仍在 不能令人满意。