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Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape
Meenakshi Hegde, … , Jordan S. Orange, Nabil Ahmed
Meenakshi Hegde, … , Jordan S. Orange, Nabil Ahmed
Published July 18, 2016
Citation Information: J Clin Invest. 2016;126(8):3036-3052. https://doi.org/10.1172/JCI83416.
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Research Article Oncology

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

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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.

Authors

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

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Figure 8

Increased accumulation of F-actin and increased polarization of the microtubular organizing center at the TanCAR-mediated IS.

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Increased accumulation of F-actin and increased polarization of the micr...
(A) Representative confocal images of TanCAR and biCAR T cells in immune conjugation with U373-GBM cells showing bright field, anti-pericentrin (blue), single-color anti–F-actin (red), anti-perforin (green), and overlay of all stains. (B) TanCAR T cells (open circles) or biCAR T cells (filled circles) were assessed for their ability to polarize to the target cell (measured by distance from the microtubular organizing center [MTOC] to the IS) and the accumulation of F-actin at the IS. Cells were imaged in Z stacks on a Leica TCS SP8 confocal microscope, Leica ×100 NA objective. Images were acquired with LAS AF software (Leica) and analyzed with Volocity software. Each data point represents an individual synapse and is a collective from 2 independent experiments. ***P < 0.0005.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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