Monzo Hector J, Kalander Kerttu, Hyytiäinen Marko M, Elbasani Endrit, Wall Johanna, Moyano-Galceran Lidia, Tanjore Ramanathan Jayendrakishore, Jukonen Joonas, Laakkonen Pirjo, Ristimäki Ari, Carlson Joseph W, Lehti Kaisa, Salehi Sahar, Puolakkainen Pauli, Haglund Caj, Seppänen Hanna, Leppä Sirpa, Ojala Päivi M
Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Mol Cancer Ther. 2023 Nov 1;22(11):1319-1331. doi: 10.1158/1535-7163.MCT-23-0008.
Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized stage-specific embryonic antigen-4 (SSEA-4) cell-surface glycolipid as a target for CAR T-cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed preclinically in vitro and in vivo for antitumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4-positive cells in all the tested cancer cell lines, whereas SSEA-4-negative cells lines were not targeted. In vivo efficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific antitumor response at all the CAR T-cell doses used. At high T-cell doses, CAR T cell-treated mice showed signs of health deterioration after a follow-up period. However, the severity of toxicity was reduced with a delayed onset when lower CAR T-cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR T-cell therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.
用于实体瘤的嵌合抗原受体（CAR）T细胞免疫疗法面临着诸如抗原表达异质性等关键挑战。我们将阶段特异性胚胎抗原-4（SSEA-4）细胞表面糖脂鉴定为CAR T细胞疗法的一个靶点。SSEA-4主要在胚胎发生过程中表达，但也在几种癌症类型中被发现，这使其成为一种有吸引力的肿瘤相关抗原。我们制备了抗SSEA-4 CAR-T细胞，并在临床前进行了体外和体内抗肿瘤反应及安全性评估。SSEA-4 CAR-T细胞有效地消除了所有测试癌细胞系中的SSEA-4阳性细胞，而SSEA-4阴性细胞系则未被靶向。使用NSG小鼠和高级别浆液性卵巢癌细胞系OVCAR4进行的体内疗效和安全性研究表明，在所有使用的CAR T细胞剂量下均出现了显著且特异性的抗肿瘤反应。在高T细胞剂量下，CAR T细胞治疗的小鼠在随访期后出现健康状况恶化的迹象。然而，当使用较低的CAR T细胞剂量时，毒性的严重程度降低且发作延迟。我们的数据证明了抗SSEA-4 CAR T细胞疗法的疗效；然而，为了其潜在的临床转化，应实施诸如剂量限制和/或为CAR-T细胞配备组合抗原识别等安全策略。
