Antigen glycosylation regulates efficacy of CAR T cells targeting CD19

Amanda Heard, Jack H. Landmann, Ava R. Hansen, Alkmini Papadopolou, Yu-Sung Hsu, Mehmet Emrah Selli, John M. Warrington, John Lattin, Jufang Chang, Helen Ha, Martina Haug-Kroeper, Balraj Doray, Saar Gill, Marco Ruella, Katharina E. Hayer, Matthew D. Weitzman, Abby M. Green, Regina Fluhrer and Nathan Singh ()
Additional contact information
Amanda Heard: Washington University School of Medicine
Jack H. Landmann: Washington University School of Medicine
Ava R. Hansen: Washington University School of Medicine
Alkmini Papadopolou: University of Augsburg
Yu-Sung Hsu: Washington University School of Medicine
Mehmet Emrah Selli: Washington University School of Medicine
John M. Warrington: Washington University School of Medicine
John Lattin: Washington University School of Medicine
Jufang Chang: Washington University School of Medicine
Helen Ha: Washington University School of Medicine
Martina Haug-Kroeper: University of Augsburg
Balraj Doray: Washington University School of Medicine
Saar Gill: University of Pennsylvania School of Medicine
Marco Ruella: University of Pennsylvania School of Medicine
Katharina E. Hayer: The Children’s Hospital of Philadelphia
Matthew D. Weitzman: The Children’s Hospital of Philadelphia
Abby M. Green: Washington University School of Medicine
Regina Fluhrer: University of Augsburg
Nathan Singh: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance to CAR therapy. Loss of SPPL3 results in hyperglycosylation of CD19, an alteration that directly inhibits CAR T cell effector function and suppresses anti-tumor cytotoxicity. Alternatively, over-expression of SPPL3 drives loss of CD19 protein, also enabling resistance. In this pre-clinical model these findings identify post-translational modification of CD19 as a mechanism of antigen escape from CAR T cell therapy.

Date: 2022
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DOI: 10.1038/s41467-022-31035-7

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