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Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia

Abstract

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19 relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.

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Fig. 1: Wild-type (WT) CD19 and the predicted mutated CD19 protein structures for the CD19/r patients.
Fig. 2: Loss of CD19 in CD19-relapsed patients is explained by CD19 loss-of-function mutations and not by exon skipping.

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Acknowledgements

The authors thank the patients and their families for participating in these clinical trials and A. Abrams for figure design.

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J.E.L., M.Q., S.A.G., M.B., B.D.M., E.R.N., H. Bittencourt, H.H., J.B., S.M.D., and M.V. contributed patient samples for sequencing. P.A.W. provided clinical data on the patients. R.J.L. oversaw the DNA- and RNA-seq. E.J.O. and M.R. analyzed and interpreted the sequencing data. X.H., P.P., and K.N. analyzed and interpreted the flow cytometry MRD assay data. W.W., J.A.E., H. Bitter, M.M., J.L.B., C.T., and S.P. provided guidance and scientific input. E.J.O. wrote the paper, with contributions from all authors.

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Correspondence to Elena J. Orlando.

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Competing interests

The research samples used in this manuscript come from patients treated on clinical trials conducted by Novartis. J.E.L., M.Q., H. Bittencourt, S.M.D, and S.A.G. consult for Novartis. E.J.O., X.H., C.T., P.A.W., R.J.L., M.R., J.L.B., H.Bitter, M.M., P.P., S.P., J.A.E., and W.W. are employed by Novartis or were employed by Novartis at the time of manuscript preparation.

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Orlando, E.J., Han, X., Tribouley, C. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med 24, 1504–1506 (2018). https://doi.org/10.1038/s41591-018-0146-z

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