Cited by 659CAR-T cell therapy researchImmunotherapy and Immune ResponsesCRISPR and Genetic Engineering

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Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell

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Ruella, Marco, Xu, Jun, Barrett, David M., Fraietta, Joseph A., Reich, Tyler J., Ambrose, David E., Klichinsky, Michael, Shestova, Olga, Patel, Prachi R., Kulikovskaya, Irina, Nazimuddin, Farzana, Bhoj, Vijay G., Orlando, Elena J., Fry, Terry J., Bitter, Hans, Maude, Shannon L., Levine, Bruce L., Nobles, Christopher L., Bushman, Frederic D., Young, Regina M., Scholler, John, Gill, Saar I., June, Carl H., Grupp, Stephan A., Lacey, Simon F., Melenhorst, J. Joseph·2018·Nature Medicine

DOI 10.1038/s41591-018-0201-9PMC PMC6511988

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Abstract

We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19- leukemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019.

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Authors: Ruella, M., Xu, J., Barrett, D. M., Fraietta, J. A., Reich, T. J., Ambrose, D. E., Klichinsky, M., Shestova, O., Patel, P. R., Kulikovskaya, I., Nazimuddin, F., Bhoj, V. G., Orlando, E. J., Fry, T. J., Bitter, H., Maude, S. L., Levine, B. L., Nobles, C. L., Bushman, F. D., Young, R. M., Scholler, J., Gill, S. I., June, C. H., Grupp, S. A., Lacey, S. F., & Melenhorst, J. J.
Affiliations: Abramson Cancer Center (US)
Children's Hospital of Philadelphia (US)
University of Pennsylvania (US)
Children's Hospital Colorado (US)
Corresponding author: June, Carl H.
Melenhorst, J. Joseph
ORCID: Ruella, Marco
Xu, Jun
Barrett, David M.
Fraietta, Joseph A.
Reich, Tyler J.
Klichinsky, Michael
Patel, Prachi R.
Kulikovskaya, Irina
Bhoj, Vijay G.
Orlando, Elena J.
Fry, Terry J.
Bitter, Hans
Maude, Shannon L.
Levine, Bruce L.
Nobles, Christopher L.
Bushman, Frederic D.
Young, Regina M.
Scholler, John
Gill, Saar I.
June, Carl H.
Grupp, Stephan A.
Lacey, Simon F.
Melenhorst, J. Joseph
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2018-10
Volume: 24
Issue: 10
Pages: 1499-1503
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-018-0201-9
PMC: PMC6511988
OpenAlex: W2893691711
Cited by: 659
References: 36
Citations by year: 2026: 61 · 2025: 73 · 2024: 83 · 2023: 84 · 2022: 83 · 2021: 91 · 2020: 91 · 2019: 78 · 2018: 14
FWCI: 25.75
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (K99CA212302, R00CA212302, T32CA009140, R01CA120409, P01CA214278)
Topics: Health Sciences › Medicine › Oncology › CAR-T cell therapy research
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Keywords: CAR T-cell therapy, CD19, tisagenlecleucel, B-cell acute lymphoblastic leukemia, CAR T cell manufacturing, relapse
MeSH terms: Receptors, Chimeric Antigen, Adult, Epitopes, B-Lymphocytes, Humans, Leukemia, Male, Receptors, Antigen, T-Cell, T-Lymphocytes, Antigens, CD19, Drug Resistance, Neoplasm, Young Adult, Cell- and Tissue-Based Therapy

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Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell

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