Yan Jun, Shi Chunhua, Yang Guojun, Tian Ze, Torikai Hiroki, Sukhumalchandra Pariya, Peng Shaohua, Chang Edward, Cui Meng, Kerros Celine, Philips Anne, Qiao Na, Zhang Mao, Lofton Timothy E, Allen Jason K, Gonzalez Michelle A, Patchametla Sathvik, Sergeeva Anna, St John Lisa, He Helen, Zha Dongxing, Molldrem Jeffrey, Alatrash Gheath
Oncology Research for Biologics and Immunotherapy Translation (ORBIT), University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Leukemia. 2025 May 28. doi: 10.1038/s41375-025-02652-0.
There has been a been a paucity of immunotherapy targets in myeloid malignancies. We identified the HLA-A2 (A2)-restricted, cathepsin G (CG)-derived signal peptide, CG1, as a promising immunotherapeutic target. CG1 is presented by HLA-A2 in acute (AML) and chronic (CML) myeloid leukemia. We previously developed a T cell receptor-mimic antibody (TCR-m) that targets CG1/A2, engineered it into a bispecific T cell engager antibody, and demonstrated its safety and efficacy in AML and CML. In this study, we provide data for the engineering, preclinical efficacy, and safety of CG1/A2-targeting chimeric antigen receptor (CAR) T cells (CG1/A2-CAR T), which utilize the CG1/A2 TCR-m constructs. We show that the CG1/A2 TCR-m has high affinity for CG1/A2 monomers and CG1/A2-expressing leukemia, including HLA-A2 AML and CML. We demonstrate potent CG1/A2 CAR T killing of HLA-A2 AML and CML both in vitro and in vivo. Importantly, we found that CG1/A2-CAR T cells did not affect normal bone marrow hematopoiesis. These results validate signal peptides as immunotherapeutic targets and provide a foundation for the continued clinical development of CG1/A2-CAR T cells in AML and CML.
髓系恶性肿瘤中的免疫治疗靶点一直较为匮乏。我们确定了HLA - A2（A2）限制性、组织蛋白酶G（CG）衍生的信号肽CG1为一个有前景的免疫治疗靶点。在急性髓系白血病（AML）和慢性髓系白血病（CML）中，CG1由HLA - A2呈递。我们之前开发了一种靶向CG1/A2的T细胞受体模拟抗体（TCR - m），并将其改造为双特异性T细胞衔接抗体，且在AML和CML中证明了其安全性和有效性。在本研究中，我们提供了利用CG1/A2 TCR - m构建体的靶向CG1/A2的嵌合抗原受体（CAR）T细胞（CG1/A2 - CAR T）的工程设计、临床前疗效和安全性数据。我们表明，CG1/A2 TCR - m对CG1/A2单体以及表达CG1/A2的白血病细胞，包括HLA - A2 AML和CML具有高亲和力。我们在体外和体内均证明了CG1/A2 CAR T对HLA - A2 AML和CML具有强大的杀伤作用。重要的是，我们发现CG1/A2 - CAR T细胞不影响正常骨髓造血。这些结果验证了信号肽作为免疫治疗靶点的可行性，并为CG1/A2 - CAR T细胞在AML和CML中的持续临床开发奠定了基础。
