Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.
Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
Cancer Immunol Res. 2021 Mar;9(3):279-290. doi: 10.1158/2326-6066.CIR-20-0280. Epub 2020 Dec 22.
Chimeric antigen receptor (CAR) T-cell therapy has had limited success in early-phase clinical studies for solid tumors. Lack of efficacy is most likely multifactorial, including a limited array of targetable antigens. We reasoned that targeting the cancer-specific extra domain B (EDB) splice variant of fibronectin might overcome this limitation because it is abundantly secreted by cancer cells and adheres to their cell surface. , EDB-CAR T cells recognized and killed EDB-positive tumor cells. , 1 × 10 EDB-CAR T cells had potent antitumor activity in both subcutaneous and systemic tumor xenograft models, resulting in a significant survival advantage in comparison with control mice. EDB-CAR T cells also targeted the tumor vasculature, as judged by IHC and imaging, and their antivascular activity was dependent on the secretion of EDB by tumor cells. Thus, targeting tumor-specific splice variants such as EDB with CAR T cells is feasible and has the potential to improve the efficacy of CAR T-cell therapy.
嵌合抗原受体 (CAR) T 细胞疗法在实体瘤的早期临床研究中收效甚微。疗效不佳很可能是多因素的，包括靶向抗原的选择有限。我们推测，针对癌症特异性的纤连蛋白外显子 D (EDB) 剪接变体可能克服这一限制，因为它在癌细胞中大量分泌并黏附在其细胞表面。结果表明，EDB-CAR T 细胞识别并杀死了 EDB 阳性的肿瘤细胞。在皮下和系统性肿瘤异种移植模型中，1×10 的 EDB-CAR T 细胞具有强大的抗肿瘤活性，与对照组小鼠相比，具有显著的生存优势。EDB-CAR T 细胞还靶向肿瘤血管，通过免疫组化和成像判断，其抗血管活性依赖于肿瘤细胞分泌的 EDB。因此，用 CAR T 细胞靶向肿瘤特异性剪接变体，如 EDB 是可行的，并有潜力提高 CAR T 细胞疗法的疗效。
