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.

  • Review Article
  • Published:

CAR T-cell therapy for the management of refractory/relapsed high-grade B-cell lymphoma: a practical overview

Abstract

The goal of this review is to firstly address the concept of chimeric antigen receptor T-cell (CAR T-cell) therapy and where it fits in the evolving landscape of the management of patients with refractory/relapsed diffuse large B-cell lymphoma. The recognition of the indications for CAR T-cell therapy for patients with aggressive B-cell lymphoma will be discussed, including a review of the algorithms and selection criteria for CAR T-cell therapy and finally, the role of bridging therapy and the timing of CAR T-cell therapy in augmenting chances of a successful outcome.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1

Similar content being viewed by others

References

  1. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9:105–16.

    Article  CAS  PubMed  Google Scholar 

  2. Pfreundschuh M, Kuhnt E, Trumper L, Osterborg A, Trneny M, Shepherd L, et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011;12:1013–22.

    CAS  PubMed  Google Scholar 

  3. Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012;13:1250–9.

    Article  CAS  PubMed  Google Scholar 

  4. Friedberg JW. Relapsed/refractory diffuse large B-cell lymphoma. Hematol Am Soc Hematol Educ Program. 2011;2011:498–505.

    Article  Google Scholar 

  5. Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, et al. Diffuse large B-cell lymphoma version 1.2016. J Natl Compr Canc Netw. 2016;14:196–231.

    Article  PubMed  Google Scholar 

  6. Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130:1800–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lerner RE, Thomas W, Defor TE, Weisdorf DJ, Burns LJ. The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin’s lymphoma in second complete or partial remission. Biol Blood Marrow Transplant. 2007;13:486–92.

    Article  PubMed  Google Scholar 

  8. Ayers EC, Li S, Medeiros LJ, Bond DA, Maddocks KJ, Torka P. et al. Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure. Cancer. 2019;126:293–303.

    Article  PubMed  Google Scholar 

  9. Nagle SJ, Woo K, Schuster SJ, Nasta SD, Stadtmauer E, Mick R, et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol. 2013;88:890–4.

    Article  CAS  PubMed  Google Scholar 

  10. Ghobadi A. Chimeric antigen receptor T cell therapy for non-Hodgkin lymphoma. Curr Res Transl Med. 2018;66:43–9.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125:4017–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hinrichs CS, Restifo NP. Reassessing target antigens for adoptive T-cell therapy. Nat Biotechnol. 2013;31:999–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gauthier J, Yakoub-Agha I. Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: clinical data to date, current limitations and perspectives. Curr Res Transl Med. 2017;65:93–102.

    Article  CAS  PubMed  Google Scholar 

  14. Grupp S. Beginning the CAR T cell therapy revolution in the US and EU. Curr Res Transl Med. 2018;66:62–4.

    Article  PubMed  Google Scholar 

  15. Ruella M, June CH. Chimeric antigen receptor T cells for B cell neoplasms: choose the right CAR for you. Curr Hematol Malig Rep. 2016;11:368–84.

    Article  PubMed  Google Scholar 

  16. Abramson JS, Gordon LI, Palomba ML, Lunning MA, Arnason JE, Forero-Torres A, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol. 2018;36:7505–7505.

    Article  Google Scholar 

  17. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45–56.

    Article  CAS  PubMed  Google Scholar 

  19. Nastoupil LJ, Jain MD, Spiegel JY, Ghobadi A, Lin Y, Dahiya S, et al. Axicabtagene ciloleucel (Axi-cel) CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: real world experience. Blood. 2018;132:91–91.

    Article  Google Scholar 

  20. Riedell PA, Walling C, Nastoupil LJ, Pennisi M, Maziarz RT, McGuirk JP, et al. A multicenter retrospective analysis of outcomes and toxicities with commercial axicabtagene ciloleucel and tisagenlecleucel for relapsed/refractory aggressive B-cell lymphomas. Biol Blood Marrow Transplant. 2020;26:S41–2.

    Article  Google Scholar 

  21. Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Ciceri F. et al. Management of adults and children undergoing CAR T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2019;105:297–316.

    Article  Google Scholar 

  22. Thieblemont C, Le Gouill S, Di Blasi R, Cartron G, Morschhauser F, Bachy E, et al. Real-world results on CD19 CAR T-cell for 60 French patients with relapsed/refractory diffuse large B-cell lymphoma included in a temporary authorization for use program. Hematological Oncol. 2019;37:301–301.

    Article  Google Scholar 

  23. Frigault MJ, Dietrich J, Martinez-Lage M, Leick M, Choi BD, DeFilipp Z. et al. Tisagenlecleucel CAR-T cell therapy in secondary CNS lymphoma. Blood. 2019;134:860–6.

  24. Bennani NN, Maurer MJ, Nastoupil LJ, Jain MD, Chavez JC, Cashen AF, et al. Experience with axicabtagene ciloleucel (Axi-cel) in patients with secondary CNS involvement: results from the US lymphoma CAR T consortium. Blood. 2019;134:763–763.

    Article  Google Scholar 

  25. Frigault MJ, Dietrich J, Martinez-Lage M, Leick M, Choi BD, DeFilipp Z, et al. Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. Blood. 2019;134:860–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sim AJ, Jain MD, Figura NB, Chavez JC, Shah BD, Khimani F, et al. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-cell lymphoma. Int J Radiat Oncol. 2019;105:1012–21.

    Article  CAS  Google Scholar 

  27. Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25:285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35:1803–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Turtle CJ, Hanafi L-AA, Berger C, Hudecek M, Pender B, Robinson E. et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8:355ra116.

  30. Turtle CJ, Hay KA, Hanafi L-A, Li D, Cherian S, Chen X. et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor–modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35:3010–20.

  31. Neelapu SS. CAR-T efficacy: is conditioning the key? Blood. 2019;133:1799–1800.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gauthier J, Turtle CJ. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr Res Transl Med. 2018;66:50–2.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62.

    Article  CAS  PubMed  Google Scholar 

  35. Novartis Pharmaceuticals Corporation. Kymriah® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.

  36. EMA. Committee for advanced therapies: guideline on the quality, non­clinical and clinical aspects of gene therapy medicinal products. Amsterdam: European Medicines Agency; 2018.

    Google Scholar 

  37. US FDA. Testing of retroviral vector-based human gene therapy products for replication competent retrovirus during product manufacture and patient follow-up (final guidance document). White Oak, MD: Food and Drug Administration; 2020.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed substantially to the conception, writing, critical review and final approval of the manuscript.

Corresponding author

Correspondence to Mohamad Mohty.

Ethics declarations

Conflict of interest

MM reports grants and/or lecture honoraria from Janssen, Sanofi, Maat Pharma, JAZZ pharmaceutical, Celgene, Amgen, BMS, Takeda, Pfizer, and Roche, all outside the submitted work. FM reports lecture honoraria from Therakos/Mallinckrodt, Biocodex, Janssen, Keocyte, Sanofi, JAZZ pharmaceutical and Astellas, all outside the submitted work. AB reports honoraria from Abbvie, Novartis, Takeda, Roche, Celgene, Pfizer, Janssen and Amgen and Research support from Novartis, Takeda, Roche, Celgene and Janssen. CC reports honoraria from Kite/Gilead and Novartis. SSK is inventor on patents and royalties licensed to Novartis, Humanigen, and Mettaforge. He receives research support from Kite, Gilead, Novartis, Juno, Celgene, Humanigen, Tolero, Lentigen, Sunesis, and Morphosys. He has served on SAB for Humanigen, Kite, and Juno. M-AP reports honoraria from Abbvie, Bellicum, Bristol-Myers Squibb, Celgene, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda. He serves on DSMBs for Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune. He has received research support for clinical trials from Incyte, Kite (Gilead) and Miltenyi. IY-A reports honorarium from Gilead/Kite, Celgene, Novartis and Jansse. The other authors did not disclose any relevant conflict of interest in relation to this work

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohty, M., Dulery, R., Gauthier, J. et al. CAR T-cell therapy for the management of refractory/relapsed high-grade B-cell lymphoma: a practical overview. Bone Marrow Transplant 55, 1525–1532 (2020). https://doi.org/10.1038/s41409-020-0892-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-020-0892-7

This article is cited by

Search

Quick links