Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia

Bone Marrow Transplantation volume 54, pages 1208–1217 (2019)Cite this article

Subjects

Abstract

The source of CAR T cells can be autologous (autoCAR) or allogeneic (alloCAR). The latter is seen in patients with a history of allogeneic hematopoietic stem cell transplantation, and can be either donor-derived (DD-alloCAR) or recipient-derived (RD-alloCAR). While autoCAR is activated by CAR only, alloCAR receives activation signals from both T-cell receptor (TCR) and CAR. As a result, the biological differences could impact clinical outcomes. We retrospectively reviewed 31 patients: 17 received autoCAR, 11 received RD-alloCAR, and 3 received DD-alloCAR. After a median follow-up of 9 months, CR rate was 88.2% (95% CI 63.6–98.5%) in autoCAR and 100% (95% CI 71.5–100%) in RD-alloCAR. The median peak expansion in the autoCAR was significantly higher than the RD-alloCAR group (p = 0.007). RD-alloCAR group had significantly less patients with severe CRS (Grade ≥ 3) than the autoCAR group (p = 0.049). Acute graft-versus-host disease (GVHD) occurred in 2 (18.2%) of RD-alloCAR patients and 1 (33.3%) of DD-alloCAR patients. Univariate subgroup analysis of alloCAR group showed the presence of cGVHD at the time of T-cell collection was significantly associated with less than 6-month relapses (p = 0.022). RD-alloCAR patients with or without cGVHD at PBMC collection did not differ regarding the peak CAR T-cell expansion, CRS grades and OS.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.

    Article  CAS  Google Scholar 

  2. Smith M, Zakrzewski J, James S, Sadelain M. Posttransplant chimeric antigen receptor therapy. Blood. 2018;131:1045–52.

    Article  CAS  Google Scholar 

  3. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–62.

    Article  CAS  Google Scholar 

  4. Collins RH, Goldstein S, Giralt S, Levine J, Porter D, Drobyski W, et al. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant. 2000;26:511–6.

    Article  Google Scholar 

  5. Roddie C, Peggs KS. Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation. Expert Opin Biol Ther. 2011;11:473–87.

    Article  Google Scholar 

  6. Yang Y, Jacoby E, Fry TJ. Challenges and opportunities of allogeneic donor-derived CAR T cells. Curr Opin Hematol. 2015;22:509–15.

    Article  CAS  Google Scholar 

  7. Harris DT, Kranz DM. Adoptive T cell therapies: a comparison of T cell receptors and chimeric antigen receptors. Trends Pharmacol Sci. 2016;37:220–30.

    Article  CAS  Google Scholar 

  8. Yang Y, Kohler ME, Chien CD, Sauter CT, Jacoby E, Yan C, et al. TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci Transl Med. 2017;9:eaag1209.

    Article  Google Scholar 

  9. Bridgeman JS, Ladell K, Sheard VE, Miners K, Hawkins RE, Price DA, et al. CD3ζ-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy. Clin Exp Immunol. 2014;175:258–67.

    Article  CAS  Google Scholar 

  10. Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013;122:2965–73.

    Article  CAS  Google Scholar 

  11. Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122:4129–39.

    Article  CAS  Google Scholar 

  12. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra225

    Article  Google Scholar 

  13. Dai H, Zhang W, Li X, Han Q, Guo Y, Zhang Y, et al. Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology. 2015;4:e1027469.

    Article  Google Scholar 

  14. Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126:3363–76.

    Article  Google Scholar 

  15. Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-Cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016;34:1112–21.

    Article  CAS  Google Scholar 

  16. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.

    Article  Google Scholar 

  17. Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.

    Article  Google Scholar 

  18. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28.

    Article  CAS  Google Scholar 

  19. Hu Y, Wu Z, Luo Y, Shi J, Yu J, Pu C, et al. Potent anti-leukemia activities of chimeric antigen receptor-modified T cells against CD19 in Chinese patients with relapsed/refractory acute lymphocytic leukemia. Clin Cancer Res. 2017;23:3297–306.

    Article  CAS  Google Scholar 

  20. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-8.

  21. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21:389–401.e381.

    Article  Google Scholar 

  22. Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139.

    Article  Google Scholar 

  23. Luo Y, Xiao H, Lai X, Shi J, Tan Y, He J, et al. T-cell-replete haploidentical HSCT with low-dose anti-T-lymphocyte globulin compared with matched sibling HSCT and unrelated HSCT. Blood. 2014;124:2735–43.

    Article  CAS  Google Scholar 

  24. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127:3321–30.

    Article  CAS  Google Scholar 

  25. Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130:2295–306.

    Article  CAS  Google Scholar 

  26. Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain MCAR. T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24:731–8.

    Article  CAS  Google Scholar 

  27. Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739–48.

    Article  CAS  Google Scholar 

  28. Hainz U, Obexer P, Winkler C, Sedlmayr P, Takikawa O, Greinix H, et al. Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation. Blood. 2005;105:4127–34.

    Article  CAS  Google Scholar 

  29. Bachireddy P, Wu CJ. Understanding anti-leukemia responses to donor lymphocyte infusion. Oncoimmunology. 2014;3:e28187.

    Article  Google Scholar 

  30. Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med. 2017;23:242–9.

    Article  CAS  Google Scholar 

  31. Cooke KR, Luznik L, Sarantopoulos S, Hakim FT, Jagasia M, Fowler DH, et al. The bbiology of cchronic graft-versus-host disease: a task force report from the national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2017;23:211–34.

    Article  Google Scholar 

  32. Guedan S, Chen X, Madar A, Carpenito C, McGettigan SE, Frigault MJ, et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood. 2014;124:1070–80.

    Article  CAS  Google Scholar 

  33. Signori A, Crocchiolo R, Oneto R, Sacchi N, Sormani MP, Fagioli F, et al. Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors. Bone Marrow Transplant. 2012;47:1474–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Qu Cui, PhD for the editorial assistance.

Funding

This work was supported by the grants from 973 Program (2015CB964900), the Natural Science Foundation of China (81470341, 81770201, 81730008), Key Project of Science and Technology Department of Zhejiang Province (2018C03016-2, 2015C03G2150011), Zhejiang public welfare foundation (GF18H180002).

Author contributions

H.H. designed the study. Y.H. and J.W. were responsible for writing the manuscript. J.W. and J.Y. collected and analyzed all data. G.W., Y.L., J.S., W.W., K.Z., L.X., Y.Z., Z.W., H.X., and A.H.C. participated in the study. All authors approved the final version of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Yongxian Hu, Jiasheng Wang

Authors and Affiliations

  1. Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China

    Yongxian Hu, Jiasheng Wang, Guoqing Wei, Jian Yu, Yi Luo, Jimin Shi, Wenjun Wu, Huijun Xu & He Huang

  2. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Zhejiang, China

    Yongxian Hu, Jiasheng Wang, Guoqing Wei, Jian Yu, Yi Luo, Jimin Shi, Wenjun Wu, Huijun Xu & He Huang

  3. Institute of Hematology, Zhejiang University, Zhejiang, China

    Yongxian Hu, Jiasheng Wang, Guoqing Wei, Jian Yu, Yi Luo, Jimin Shi, Wenjun Wu, Huijun Xu & He Huang

  4. PETCT Center, Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China

    Kui Zhao

  5. Innovative Cellular Therapeutics Co. Ltd, Shanghai, China

    Lei Xiao & Zhao Wu

  6. Shanghai YaKe Biotechnology Ltd, Shanghai, China

    Yanlei Zhang & Alex Hongsheng Chang

Authors
  1. Yongxian Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiasheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guoqing Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jian Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jimin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenjun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lei Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yanlei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Huijun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alex Hongsheng Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. He Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to He Huang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was conducted according to the ethical principles for medical research involving human subjects as stated in the Declaration of Helsinki. The study protocol was reviewed and approved by the Institutional Review Boards of the First Affiliated Hospital, School of Medicine, Zhejiang University. All participants signed informed consent.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, Y., Wang, J., Wei, G. et al. A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia. Bone Marrow Transplant 54, 1208–1217 (2019). https://doi.org/10.1038/s41409-018-0403-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0403-2

This article is cited by

Search

Advanced search

Quick links