Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia (original) (raw)

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• 05 February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41591-021-01248-2

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Acknowledgements

We thank the patients for their participation in the clinical trials from which research samples were obtained. We also acknowledge A. Fesnak, A. Lamontagne, A. Malykhin, C. Corl, Y. Ohayon and other members of the Clinical Cell and Vaccine Production Facility for cell manufacturing and testing. In addition, we are grateful to V. Gonzalez, J. Finklestein, F. Nazimuddin, J.-M. Navenot, M. Bogush, Y. Tanner, N. Kengle, K. Marcucci, A. Chew, C. Pletcher, P. Hallberg and R. Schretzenmair for contributions to correlative studies and/or other research support. D. Campana, C. Imai and others at St. Jude Children’s Research Hospital designed, developed and provided, under material-transfer agreements, the CAR used in this study. B. Jena and L. Cooper (MD Anderson Cancer Center) are acknowledged for providing the CAR anti-idiotype detection reagent. The functional anti-idiotypic antibody that was used for in vitro CAR stimulation experiments was a kind gift from Novartis Pharmaceutical Corporation. This work was supported by funding from NCI T32CA009140 (J.A.F.) R01CA165206 (D.L.P. and C.H.J.), P01CA214278 (C.H.J), a Stand Up to Cancer Phillip A. Sharp Innovation in Collaboration Award (C.H.J) and Novartis.

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Author notes

1. These authors contributed equally: Simon F. Lacey and Elena J. Orlando.

Authors and Affiliations

1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
   Joseph A. Fraietta, Simon F. Lacey, F. Brad Johnson, Megan M. Davis, Bruce L. Levine, Donald L. Siegel, David L. Porter, Carl H. June & J. Joseph Melenhorst
2. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
   Joseph A. Fraietta, Simon F. Lacey, Mercy Gohil, Stefan Lundh, Alina C. Boesteanu, Yan Wang, Roddy S. O’Connor, Edward Pequignot, David E. Ambrose, Changfeng Zhang, Nicholas Wilcox, Felipe Bedoya, Corin Dorfmeier, Fang Chen, Lifeng Tian, Harit Parakandi, Minnal Gupta, Regina M. Young, Irina Kulikovskaya, Li Liu, Jun Xu, Megan M. Davis, Bruce L. Levine, Noelle V. Frey, Donald L. Siegel, Carl H. June & J. Joseph Melenhorst
3. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
   Joseph A. Fraietta, Simon F. Lacey, Alexander C. Huang, E. John Wherry, Carl H. June & J. Joseph Melenhorst
4. Novartis Institutes for BioMedical Research, Cambridge, MA, USA
   Elena J. Orlando, Iulian Pruteanu-Malinici, Sadik H. Kassim, Hans Bitter & Jennifer L. Brogdon
5. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
   Wei-Ting Hwang
6. Division of Hematology-Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA
   Noelle V. Frey & David L. Porter
7. Division of Transfusion Medicine and Therapeutic Pathology, University of Pennsylvania, Philadelphia, PA, USA
   Donald L. Siegel
8. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
   Alexander C. Huang & E. John Wherry

Authors

1. Joseph A. Fraietta
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2. Simon F. Lacey
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3. Elena J. Orlando
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4. Iulian Pruteanu-Malinici
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5. Mercy Gohil
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6. Stefan Lundh
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7. Alina C. Boesteanu
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8. Yan Wang
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9. Roddy S. O’Connor
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10. Wei-Ting Hwang
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11. Edward Pequignot
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12. David E. Ambrose
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13. Changfeng Zhang
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14. Nicholas Wilcox
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15. Felipe Bedoya
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16. Corin Dorfmeier
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17. Fang Chen
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18. Lifeng Tian
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19. Harit Parakandi
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20. Minnal Gupta
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21. Regina M. Young
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22. F. Brad Johnson
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23. Irina Kulikovskaya
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24. Li Liu
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25. Jun Xu
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26. Sadik H. Kassim
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27. Megan M. Davis
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28. Bruce L. Levine
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29. Noelle V. Frey
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30. Donald L. Siegel
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31. Alexander C. Huang
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32. E. John Wherry
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33. Hans Bitter
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34. Jennifer L. Brogdon
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35. David L. Porter
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36. Carl H. June
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37. J. Joseph Melenhorst
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Contributions

J.A.F., S.F.L., F.B.J., R.M.Y., N.V.F., B.L.L., D.L.S., E.J.W., J.L.B., D.L.P., C.H.J. and J.J.M. designed the experiments and/or performed analysis. J.A.F., M.Gohil, S.L., A.C.B., Y.W., R.S.O., D.E.A., C.Z., N.W., F.B., C.D., F.C., L.T., H.P., M. Gupta, I.K., L.L., J.X., S.H.K., M.M.D. and A.C.H. performed experiments. E.J.O. and H.B. analyzed RNA-seq. data. I.P.-M. carried out the computational analyses of flow cytometric data. W.-T.H. and E.P. performed statistical analyses. J.A.F., C.H.J. and J.J.M. wrote the paper, and all authors contributed to writing and providing feedback.

Corresponding author

Correspondence toJ. Joseph Melenhorst.

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Competing interests

J.A.F., S.F.L., F.B., R.M.Y., B.L.L., J.L.B., D.L.P., C.H.J. and J.J.M. hold patents related to CTL019 cell therapy. These authors declare no additional interests. The remaining authors declare no competing interests.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Tables 1, 7, 9, 10

Reporting Summary

Supplementary Table 2

Treatment and clinical characteristics of responding patients.

Supplementary Table 3

Genes differentially expressed in pre-infusion CAR T cells between CR/PRTD and PR/NR patients.

Supplementary Table 4

List of leading edge genes associated with the gene sets of Figure 2c.

Supplementary Table 5

Transcriptomic profiling of mock-stimulated (control) and CAR-stimulated CTL019 infusion products as well as ex vivo CD3+ T cells (leukapheresis).

Supplementary Table 6

Phenotypes of leukapheresed CD8+ and CD4+ T cells identified by the flowType analysis that segregate CR from NR patients.

Supplementary Table 8

Phenotypes of CD8+ T cells in the CAR T cell infusion product identified by the flowType analysis that segregate CR from NR patients.

Supplementary Table 11

Holm-Sidak adjusted P values and summary statistics for data sets involving multiple comparisons.

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Fraietta, J.A., Lacey, S.F., Orlando, E.J. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.Nat Med 24, 563–571 (2018). https://doi.org/10.1038/s41591-018-0010-1

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• Received: 29 September 2017
• Accepted: 07 February 2018
• Published: 30 April 2018
• Issue Date: May 2018
• DOI: https://doi.org/10.1038/s41591-018-0010-1