抗原
嵌合抗原受体
癌症研究
T细胞
细胞毒性T细胞
肿瘤抗原
免疫疗法
免疫系统
生物
化学
分子生物学
细胞生物学
免疫学
生物化学
体外
作者
Meenakshi Hegde,Malini Mukherjee,Zakaria Grada,Antonella Pignata,Daniel Landi,Shoba Navai,Amanda Wakefield,Kristen Fousek,Kevin Bielamowicz,Kevin Chow,Vita S. Brawley,Tiara Byrd,Simone Krebs,Stephen Gottschalk,Winfried S. Wels,Matthew L. Baker,Gianpietro Dotti,Maksim Mamonkin,Malcolm K. Brenner,Jordan S. Orange,Nabil Ahmed
摘要
In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
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