Niu Wenhao, Wang Binchen, Zhang Yirui, Wang Chaomin, Cao Jing, Li Jiali, He Yong, Lei Ping
Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Nuclear Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
Front Immunol. 2024 Jul 17;15:1433679. doi: 10.3389/fimmu.2024.1433679. eCollection 2024.
Fibroblast activation protein (FAP) overexpression on cancer-associated fibroblasts (CAFs) is associated with poor prognosis and worse clinical outcomes. Selective ablation of pro-tumorgenic FAP stromal cells with CAR-T cells may be a new therapeutic strategy. However, the clinical use of FAP-CAR T cells is suggested to proceed with caution for occasional poor efficacy and induction of on-target off-tumor toxicity (OTOT), including lethal osteotoxicity and cachexia. Hence, more investigations and preclinical trials are required to optimize the FAP-CAR T cells and to approve their safety and efficacy.
In this study, we designed second-generation CAR T cells targeting FAP with 4-1BB as a co-stimulatory molecule, and tested their cytotoxicity against FAP-positive cells (hFAP-HT1080 cells and a variety of primary CAFs) and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model.
Results showed that our FAP-CAR T cells were powerfully potent in killing human and murine FAP-positive tumor cells and CAFs in multiple types of tumors in BALB/c and C57BL/6 mice and in patient-derived xenografts (PDX) model. And they were proved to be biologically safe and exhibit low-level OTOT.
Taken together, the human/murine cross-reactive FAP-CAR T cells were powerfully potent in killing human and murine FAP positive tumor cells and CAFs. They were biologically safe and exhibit low-level OTOT, warranting further clinical investigation into our FAP-CAR T cells.
癌症相关成纤维细胞（CAF）上的成纤维细胞活化蛋白（FAP）过表达与预后不良和更差的临床结果相关。用嵌合抗原受体T细胞（CAR-T）选择性清除促肿瘤的FAP基质细胞可能是一种新的治疗策略。然而，由于偶尔疗效不佳以及诱导靶上脱瘤毒性（OTOT），包括致命的骨毒性和恶病质，建议谨慎进行FAP-CAR T细胞的临床应用。因此，需要更多的研究和临床前试验来优化FAP-CAR T细胞并验证其安全性和有效性。
在本研究中，我们设计了以4-1BB作为共刺激分子靶向FAP的第二代CAR T细胞，并在细胞系衍生异种移植（CDX）和患者衍生异种移植（PDX）模型中测试了它们对FAP阳性细胞（hFAP-HT1080细胞和多种原代CAF）的细胞毒性。
结果表明，我们的FAP-CAR T细胞在BALB/c和C57BL/6小鼠的多种肿瘤类型以及患者衍生异种移植（PDX）模型中，对人和小鼠FAP阳性肿瘤细胞和CAF具有强大的杀伤能力。并且它们被证明具有生物学安全性，且表现出低水平的OTOT。
综上所述，人/鼠交叉反应性FAP-CAR T细胞在杀伤人和小鼠FAP阳性肿瘤细胞和CAF方面具有强大的能力。它们具有生物学安全性，且表现出低水平的OTOT，值得对我们的FAP-CAR T细胞进行进一步的临床研究。
