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

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 ep...

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Published inNature medicine Vol. 24; no. 10; pp. 1499 - 1503
Main Authors 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
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.10.2018
Nature Publishing Group
Subjects
631/154/51/201
631/250/251
692/53/2423
Adult
Antigenic determinants
Antigens
Antigens, CD19 - immunology
Antigens, CD19 - therapeutic use
B cells
B-Lymphocytes - immunology
Biomedical and Life Sciences
Biomedicine
Brief Communication
Cancer recurrence
Cancer Research
CAR gene
Case studies
CD19 antigen
Cell- and Tissue-Based Therapy
Chemotherapy
Chimeric antigen receptors
Complications and side effects
Drug Resistance, Neoplasm - immunology
Epitopes
Epitopes - immunology
Genes
Health aspects
Humans
Infectious Diseases
Leukemia
Leukemia - drug therapy
Leukemia - immunology
Leukemia - pathology
Lymphocytes
Lymphocytes B
Lymphocytes T
Male
Masking
Medical schools
Metabolic Diseases
Molecular Medicine
Neurosciences
Production management
Receptors, Antigen, T-Cell - immunology
Receptors, Antigen, T-Cell - therapeutic use
Receptors, Chimeric Antigen
Recurrence (Disease)
T cell antigen receptors
T cells
T-Lymphocytes - immunology
Young Adult
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Summary: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. A CAR gene unintentionally introduced in a contaminating leukemia cell during the manufacturing of CAR T cells caused a patient to relapse after therapy.
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M.R., J.X., D.M.B., T.J.R., S.I.G., S.A.G., C.H.J., S.F.L., and J.J.M formulated the ideas and planned the experiments. M.R., J.X., D.M.B., T.J.R., M.K., O.S., F.N., D.E.A., I.K., J.A.F., J.S., PR.P, V.G.B., C.L.N., F.D.B. E.J.O., and H.B. performed the experiments, analyzed the data, and contributed to the manuscript. J.X, M.K., and T.J.R. performed the confocal imaging. C.L.N. and F.D.B. performed the lentivirus integration site analysis. S.L.M., D.M.B., and S.A.G. managed Patient #107 in the clinic. M.R., J.J.M, and S.F.L. wrote the manuscript; S.A.G., B.L.L., R.M.Y., J.S., and C.H.J. edited the manuscript. D.M.B., M.R., and O.S. performed the animal experiments. T.J.F provided clinical care and identified CARB recurrence. All the authors reviewed and accepted the contents of the article. M.R., J.X, and D.M.B equally contributed to this manuscript. S.F.L and J.J.M. share senior authorship.
Author contributions
ISSN:1078-8956
1546-170X
1546-170X
DOI:10.1038/s41591-018-0201-9