ORAL PRESENTATION Open Access

A bispecific chimeric antigen receptor moleculeenhances T cell activation through dualimmunological synapse formation and offsetsantigen escape in glioblastomaMeenakshi Hegde1*, Zakaria Grada1, Antonella Pignata1, Amanda Wakefield1, Kristen Fousek1, Kevin Bielamowicz1,Kevin Chow1, Vita Brawley1, Tiara Byrd1, Stephen Gottschalk1, Malini Mukherjee1, Winfried S Wels2, Matthew Baker1,Giapietro Dotti1, Jordan Orange1, Nabil Ahmed1

From 30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)National Harbor, MD, USA. 4-8 November 2015

BackgroundAntigen escape tumor cell variants prevail in tumorsrecurring after treatment with chimeric antigen receptor(CAR) T cells with a single specificity. Recurrent tumorspreserve alternative non-targeted tumor associatedantigens.

HypothesisA bispecific CAR will mitigate antigen escape enhancingthe antitumor activity of T cells.

Methods and resultsHER2 and IL13Ra2 are currently targeted in Phase Iglioblastoma (GBM) trials using CAR T cells. We cre-ated a bispecific CAR molecule with a HER2-specificscFv joined in tandem to an IL13Ra2-binding moiety inthe CAR exodomain (Tandem CAR) and a CD28.ζ sig-naling endodomain. We used computational modelingto interrogate this design. GBM patients’ Tandem CART cells showed distinct binding to soluble HER2 andIL13Ra2 and killed primary autologous GBM cells.Three-dimensional reconstitution and quantification ofconfocal images of the Tandem CAR T cell/tumor inter-face revealed enhanced bifunctional immunologicalsynapses compared to conventional CARs. Further, Tan-dem CAR T cells exhibited significantly enhanced inex-haustible activation dynamics when compared toconventional HER2 or IL13Ra2 CAR T cells and better

controlled established GBM in an orthotopic murinemodel by offsetting both HER2 and IL13Ra2 escape.

ConclusionTandem chimeric antigen receptors enhance T cell acti-vation and mitigate antigen escape through bifunctionalimmunological synapse formation in GBM.

Authors’ details1Baylor College of Medicine, Houston, TX, USA. 2Georg-Speyer-Haus, Institutefor Tumor Biology and Experimental Therapy, Frankfurt, Germany.

Published: 4 November 2015

doi:10.1186/2051-1426-3-S2-O3Cite this article as: Hegde et al.: A bispecific chimeric antigen receptormolecule enhances T cell activation through dual immunologicalsynapse formation and offsets antigen escape in glioblastoma. Journalfor ImmunoTherapy of Cancer 2015 3(Suppl 2):O3.

1Baylor College of Medicine, Houston, TX, USAFull list of author information is available at the end of the article

Hegde et al. Journal for ImmunoTherapy of Cancer 2015, 3(Suppl 2):O3http://www.immunotherapyofcancer.org/content/3/S2/O3

© 2015 Hegde et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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