Skip to main content
SpringerLink
Log in

Anti-CD19 Chimeric Antigen Receptor T Cell Therapies: Harnessing the Power of the Immune System to Fight Diffuse Large B Cell Lymphoma

  • B-cell NHL, T-cell NHL, and Hodgkin Lymphoma (J Amengual, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This article will review the use of anti-CD19 CAR-T therapy used in relapsed/refractory diffuse large B cell lymphoma.

Recent Findings

The clinical outcomes, safety analysis, and other relevant considerations will be discussed with an emphasis on the most recently published data regarding the ZUMA-1, JULIET, and TRANSCEND NHL-001 trials.

Summary

Anti-CD19 CAR-T therapy is an exciting new therapy now approved and available to patients with relapsed/refractory diffuse large B cell lymphoma. Secondary to the increasing success and availability of these products, caregivers should expect to become familiar with the indications, toxicity, and limitations of these treatment options and when patients should be considered for referral.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gisselbrecht C, Glass B, Mounier N, Gill DS, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–90.

    Article  Google Scholar 

  2. • 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:blood-2017-03-769620. This study outlined the poor outcomes in patients diagnosed with refractory NHL and highlighted the need for better therapeutic options in this high-risk population.

  3. June CH, Riddell SR, Schumacher TN. Adoptive cellular therapy: a race to the finish line. Sci Transl Med. 2015;7(280):280ps7.

    Article  Google Scholar 

  4. Geldres C, Savoldo B, Dotti G, editors. Chimeric antigen receptor-redirected T cells return to the bench. Semin Immunol; 2016: Elsevier.

  5. Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013;10(5):267–76.

    Article  CAS  Google Scholar 

  6. Scheuermann R, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leukemia & lymphoma. 1995;18(5–6):385–97.

    Article  CAS  Google Scholar 

  7. Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat Biotechnol. 2002;20(1):70–5.

    Article  CAS  Google Scholar 

  8. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically-engineered to recognize CD19. Blood. 2010:blood-2010-04-281931.

  9. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33.

    Article  CAS  Google Scholar 

  10. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.

    Article  CAS  Google Scholar 

  11. Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011:blood-2011-04-348540.

  12. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–9.

    Article  CAS  Google Scholar 

  13. Dardonville Q, Davoine C, Dahan M, Grosjean G, Bermudez E, Ifrah N, et al. Chimeric antigen receptor-t cells (CAR-T) horizon scanning: emerging targets in oncology and hematology. Am Soc Clin Oncol; 2018.

  14. •• 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(26):2531–44 This phase 2 study helped validate the efficacy of CD19-targeted CAR-T therapy in patients diagnosed with refractory diffuse large B cell lymphoma.

    Article  Google Scholar 

  15. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Am Soc Hematology; 2017.

  16. Schuster S, Bishop MR, Tam C, Waller EK, Borchmann P, McGuirk J, et al. Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL)—an interim analysis. Hematol Oncol. 2017;35:27.

    Article  Google Scholar 

  17. • 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. Am Soc Clin Oncol; 2018. This study demonstrated Liso-Cel shows durable responses in patients with heavily pretreated R/R DLBCL.

  18. Kochenderfer JN, Somerville RP, Lu T, Yang JC, Sherry RM, Feldman SA, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther. 2017;25(10):2245–53.

    Article  CAS  Google Scholar 

  19. Kochenderfer JN, Somerville RP, 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 Off J Am Soc Clin Oncol. 2017;35(16):1803–13.

    Article  CAS  Google Scholar 

  20. Locke FL, Ghobadi A, Jacobson CA, Jacobsen ED, Miklos DB, Lekakis LJ, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B-cell lymphoma. Am Soc Clin Oncol; 2018.

  21. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Reagan PM, Miklos DB, et al. A comparison of one year outcomes in ZUMA-1 (axicabtagene ciloleucel) and SCHOLAR-1 in patients with refractory, aggressive non-Hodgkinlymphoma (NHL). Am Soc Hematology; 2017.

  22. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobsen ED, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-Cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Am Soc Hematology; 2017.

  23. •• Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54 This single institution case series of CTL019 demonstrated the durability of response that may be observed in patients obtaining a complete response with CD19 CAR-T cell therapy.

    Article  Google Scholar 

  24. Turtle CJ, Hanafi L-A, 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(355):355ra116.

    Article  Google Scholar 

  25. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Wang M, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort. Am Soc Hematology; 2017.

  26. Abramson JS, Palomba L, Gordon LI, Lunning M, Arnason J, Forero-Torres A, et al. Transcend NHL 001: immunotherapy with the CD19-directed CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Am Soc Hematol; 2016.

  27. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016:blood-2016-04-703751.

  28. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. How I treat: current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014:blood-2014-05-552729.

  29. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.

    Article  CAS  Google Scholar 

  30. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor–transduced T cells. Blood. 2011:blood-2011-10-384388.

  31. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J (Sudbury, Mass). 2014;20(2):119.

    Article  CAS  Google Scholar 

  32. 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(1):47–62.

    Article  CAS  Google Scholar 

  33. Schwartz RN, Stover PL, Dutcher JP. Managing toxicities of high-dose interleukin-2. interventions (Table 3). 2002;13:14.

  34. Goebeler M-E, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. J Clin Oncol. 2016;34(10):1104–11.

    Article  CAS  Google Scholar 

  35. Czock D, Keller F, Rasche FM, Häussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61–98.

    Article  CAS  Google Scholar 

  36. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Forero-Torres A, et al. CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001). Am Soc Clin Oncol; 2017.

  37. Ranganathan R. Chimeric antigen receptor T cells targeting the lambda light chain of human immunoglobulin as a viable target for B cell non-Hodgkin lymphoma. Am Soc Clin Oncol; 2018.

  38. Olson NE, Ragan SP, Ponko S, Trede NS, Stern HM, Sutherland CL. Tumor gene signature associated with neurotoxicity in R/R B-ALL patients treated with JCAR015, a CD19-directed CAR T cell product. Am Soc Clin Oncol; 2018.

  39. Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Clinical and biologic covariates of outcomes in ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (r-NHL). Ame Soc Clin Oncol; 2017.

  40. Wu C-Y, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule–gated chimeric receptor. Science. 2015;350(6258):aab4077.

    Article  Google Scholar 

  41. Gilbert A, Santoro S, Tse T, Candelario-Chopra T, Gomes T, Campos J, et al. Evaluating the reversible control of an engineered CAR T cell ON-switch. Am Soc Clin Oncol; 2017.

  42. Bauche C. Development of a new switchable CAR system. J Clin Oncol. 2015;36(e14024-e14024).

  43. Ying ZT, Long L, Liu H, Zhang M, He P, Rizzieri D, et al. ET190L1-ARTEMIS T cell therapy to induce complete remission of relapsed and refractory (r/r) B-cell lymphoma with no cytokine release syndrome in the first-in-human clinical study. Am SocClin Oncol; 2018.

  44. Brudno JN, Hartman SD, Pittaluga S, Stroncek D, Lam N, Kanakry JA, et al. Clinical anti-lymphoma activity and toxicity of T cells expressing a novel anti-CD19 chimeric antigen receptor with fully-human variable regions. Am Soc Clin Oncol; 2018.

  45. Siddiqi T, Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, et al. Correlation of patient characteristics and biomarkers with clinical outcomes of JCAR017 in R/R aggressive B-NHL (TRANSCEND NHL 001 study). Am Soc Clin Oncol; 2018.

  46. Sarkar R, Gloude NJ, Murphy JD. Cost-effectiveness of chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory acute lymphoblastic leukemia. Am Soc Clin Oncol; 2018.

  47. Snider JT, Brauer M, Batt K, Karaca-Mandic P, Zhang J, Goldman DP. The social value of tisagenlecleucel, a CAR-T cell therapy, for the treatment of relapsed or refractory pediatric acute lymphoblastic leukemia in the United States: what are consequences of treatment delays? : Am Soc Clin Oncol; 2018.

  48. Oluwole OO, Bishop MR, Gisselbrecht C, Gordon LI, Kersten MJ, Maloney DG, et al. ZUMA-7: a phase 3 randomized trial of axicabtagene ciloleucel (Axi-Cel) versus standard-of-care (SOC) therapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Am Soc Clin Oncol; 2018.

  49. Gauthier J HA, Hay K, et al. Factors associated with duration of response after CD19-specific CAR-T cell therapy for refractory/relapsed B-cell non-Hodgkin lymphoma. J Clin Oncol.36(abtr 7567).

  50. Mueller KT, Grupp SA, Maude SL, Levine JE, Pulsipher M, Boyer MW, et al. Immunogenicity of tisagenlecleucel in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) patients. Am Soc Clin Oncol; 2018.

  51. Yao Y, Yao X, Zhu S, Zhu W, Li Z, Wang Q, et al. Target cell killing effects of CD20 targeting chimeric antigen receptor T cells derived from the type II anti-CD20 antibody. Am Soc Clin Oncol; 2017.

  52. Dufort F, Su L, Wu L, Birt A, Lobb R, Ambrose C, et al. Activity of CAR19 T cells secreting impact fusion proteins against hematopoietic and solid tumors. Am Soc Clin Oncol; 2018.

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, 1950 Circle of Hope, Salt Lake City, UT, 84112, USA

    Robert Havard & Deborah M. Stephens

Authors
  1. Robert Havard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deborah M. Stephens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Deborah M. Stephens.

Additional information

This article is part of the Topical Collection on B-cell NHL, T-cell NHL, and Hodgkin Lymphoma

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Havard, R., Stephens, D.M. Anti-CD19 Chimeric Antigen Receptor T Cell Therapies: Harnessing the Power of the Immune System to Fight Diffuse Large B Cell Lymphoma. Curr Hematol Malig Rep 13, 534–542 (2018). https://doi.org/10.1007/s11899-018-0482-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-018-0482-6

Keywords

Search

Navigation