First published July 2, 2019 - More info
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.
Meenakshi Hegde, Malini Mukherjee, Zakaria Grada, Antonella Pignata, Daniel Landi, Shoba A. Navai, Amanda Wakefield, Kristen Fousek, Kevin Bielamowicz, Kevin K.H. Chow, Vita S. Brawley, Tiara T. Byrd, Simone Krebs, Stephen Gottschalk, Winfried S. Wels, Matthew L. Baker, Gianpietro Dotti, Maksim Mamonkin, Malcolm K. Brenner, Jordan S. Orange, Nabil Ahmed
Original citation: J Clin Invest. 2016;126(8):3036–3052. https://doi.org/10.1172/JCI83416
Citation for this expression of concern: J Clin Invest. https://doi.org/10.1172/JCI131246
A reader recently alerted the Journal that two images in this JCI article appear similar to images subsequently published in a Neuro-Oncology paper from the same lab as unique samples (1). Specifically, in Figure 9D of the JCI paper, the image for IL13Rα2 staining for the HER2 CAR sample appears to be similar to the image for EphA2 staining of a nontransduced T cell–treated sample published in Figure 6A of the Neuro-Oncology paper. In addition, in Figure 9D of the JCI paper, the image for IL13Rα2 staining for the tumor sample appears to be similar to the image for HER2 staining of a nontransduced T cell–treated sample in Figure 6B of the Neuro-Oncology paper. An institutional investigation into this matter is ongoing, and we will inform our readers of the outcome when the investigation is complete.
See the related article at Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.