PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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) in vitro and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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) in vitro and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■成纤维细胞活化蛋白(FAP)在癌症相关成纤维细胞(CAF)上的过表达与不良预后和更差的临床结果相关。用CAR-T细胞选择性消融促瘤FAP+基质细胞可能是一种新的治疗策略。然而,FAP-CART细胞的临床使用建议谨慎进行，因为偶尔效果不佳，并诱导靶向肿瘤外毒性（OTOT），包括致命的骨毒性和恶病质.因此，需要更多的研究和临床前试验来优化FAP-CART细胞并批准其安全性和有效性.
■在这项研究中，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，并在体外和细胞系来源的异种移植物（CDX）和患者来源的异种移植物（PDX）模型中测试了它们对FAP阳性细胞（hFAP-HT1080细胞和各种原代CAF）的细胞毒性。
■结果表明，我们的FAP-CART细胞在BALB/c和C57BL/6小鼠和患者衍生的异种移植物（PDX）模型中的多种肿瘤中具有强大的杀伤人和鼠FAP阳性肿瘤细胞和CAF的能力。它们被证明是生物安全的，并且表现出低水平的OTOT。
■放在一起，人/鼠交叉反应性FAP-CART细胞在杀伤人和鼠FAP阳性肿瘤细胞和CAFs方面非常有效.它们是生物安全的，表现出低水平的OTOT，保证对我们的FAP-CART细胞进行进一步的临床研究。
■在这项研究中，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，并在体外和细胞系来源的异种移植物（CDX）和患者来源的异种移植物（PDX）模型中测试了它们对FAP阳性细胞（hFAP-HT1080细胞和各种原代CAF）的细胞毒性。
■结果表明，我们的FAP-CART细胞在BALB/c和C57BL/6小鼠和患者衍生的异种移植物（PDX）模型中的多种肿瘤中具有强大的杀伤人和鼠FAP阳性肿瘤细胞和CAF的能力。它们被证明是生物安全的，并且表现出低水平的OTOT。
■放在一起，人/鼠交叉反应性FAP-CART细胞在杀伤人和鼠FAP阳性肿瘤细胞和CAFs方面非常有效.它们是生物安全的，表现出低水平的OTOT，保证对我们的FAP-CART细胞进行进一步的临床研究。
