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- Title
Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.
- Authors
Hegde, Meenakshi; Mukherjee, Malini; Grada, Zakaria; Pignata, Antonella; Landi, Daniel; Navai, Shoba A.; Wakefield, Amanda; Fousek, Kristen; Bielamowicz, Kevin; Chow, Kevin K. H.; Brawley, Vita S.; Byrd, Tiara T.; Krebs, Simone; Gottschalk, Stephen; Weis, Winfried S.; Baker, Matthew L.; Dotti, Gianpietro; Mamonkin, Maksim; Brenner, Malcolm K.; Orange, Jordan S.
- Abstract
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.
- Subjects
GLIOBLASTOMA multiforme; GLIOMAS; CANCER relapse; T cells; TUMOR antigens
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 8, p3036
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI83416