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Novel high-affinity EGFRvIII-specific chimeric antigen receptor T cells effectively eliminate human glioblastoma

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posted on 28.06.2021, 05:25 by RC Abbott, DJ Verdon, FM Gracey, HE Hughes-Parry, M Iliopoulos, KA Watson, M Mulazzani, K Luong, C D’Arcy, LC Sullivan, BR Kiefel, RS Cross, Misty Jenkins
Objectives: The increasing success of Chimeric Antigen Receptor (CAR) T cell therapy in haematological malignancies is reinvigorating its application in many other cancer types and with renewed focus on its application to solid tumors. We present a novel CAR against glioblastoma, an aggressive, malignant glioma, with a dismal survival rate for which treatment options have remained unchanged for over a decade. Methods: We use the human Retained Display (ReD) antibody platform (Myrio Therapeutics) to identify a novel single-chain variable fragment (scFv) that recognises epidermal growth factor receptor mutant variant III (EGFRvIII), a common and tumor-specific mutation found in glioblastoma. We use both in vitro functional assays and an in vivo orthotopic xenograft model of glioblastoma to examine the function of our novel CAR, called GCT02, targeted using murine CAR T cells. Results: Our EGFRvIII-specific scFv was found to be of much higher affinity than reported comparators reverse-engineered from monoclonal antibodies. Despite the higher affinity, GCT02 CAR T cells kill equivalently but secrete lower amounts of cytokine. In addition, GCT02-CAR T cells also mediate rapid and complete tumor elimination in vivo. Conclusion: We present a novel EGFRvIII-specific CAR, with effective antitumor functions both in in vitro and in a xenograft model of human glioblastoma.

Funding

We thank the following for financial support: NHMRC, Robert Connor Dawes Foundation, Carrie's Beanies for Brain Cancer and Isabella and Marcus Foundation. We thank Rodney Luwor (Royal Melbourne Hospital, the University of Melbourne) for providing cell lines. MRJ is funded by NHMRC Investigator Grant (APP1172858). RSC is funded by Cure Brain Cancer Foundation Fellowship.

History

Publication Date

09/05/2021

Journal

Clinical and Translational Immunology

Volume

10

Issue

5

Article Number

e1283

Pagination

22p.

Publisher

Wiley

ISSN

2050-0068

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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