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Acute lymphoblastic leukemia

High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients

Abstract

Refractory or relapsed B lymphoblastic leukemia (B-ALL) patients have a dismal outcome with current therapy. We treated 42 primary refractory/hematological relapsed (R/R) and 9 refractory minimal residual disease by flow cytometry (FCM-MRD+) B-ALL patients with optimized second generation CD19-directed CAR-T cells. The CAR-T-cell infusion dosages were initially ranged from 0.05 to 14 × 105/kg and were eventually settled at 1 × 105/kg for the most recent 20 cases. 36/40 (90%) evaluated R/R patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), and 9/9 (100%) FCM-MRD+ patients achieved MRD. All of the most recent 20 patients achieved CR/CRi. Most cases only experienced mild to moderate CRS. 8/51 cases had seizures that were relieved by early intervention. Twenty three of twenty seven CR/CRi patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HCT) remained in MRD with a median follow-up time of 206 (45–427) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed. Our results indicate that a low CAR-T-cell dosage of 1 × 105/kg, is effective and safe for treating refractory or relapsed B-ALL, and subsequent allo-HCT could further reduce the relapse rate.

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References

  1. Yan-Li Zhao, Tong Wu, Yue Lu, Xing-Yu Cao, De-Yan Liu, Min Xiong et al. Improved outcomes of haploidentical blood and marrow transplantation in hematologic malignancies: a single center study of 514 cases. Blood 2015; 126: 3224.

    Google Scholar 

  2. Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll W et al. Risk factors and timing of relapse after allogeneic transplantation in pediatric ALL: for whom and when should interventions be tested? Bone Marrow Transplant 2015; 50: 1173–1179.

    Article  CAS  Google Scholar 

  3. Gross G, Waks T, Eshhar Z . Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 1989; 86: 10024–10028.

    Article  CAS  Google Scholar 

  4. Irving BA, Weiss A . The cytoplasmic domain of the T cell receptor ζ chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 1991; 64: 891–901.

    Article  CAS  Google Scholar 

  5. Uckun FM, Jaszcz W, Ambrus JL, Fauci AS, Gajl-Peczalska K, Song CW et al. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood 1988; 71: 13–29.

    CAS  PubMed  Google Scholar 

  6. 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: 725–733.

    Article  CAS  Google Scholar 

  7. Sadelain M, Brentjens R, Riviere I . The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol 2009; 21: 215–223.

    Article  CAS  Google Scholar 

  8. Kershaw MH, Teng MWL, Smyth MJ, Darcy PK . Supernatural T cells: genetic modification of T cells for cancer therapy. Nat Rev Immunol 2005; 5: 928–940.

    Article  CAS  Google Scholar 

  9. 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; 116: 4099–4102.

    Article  CAS  Google Scholar 

  10. 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: 1507–1517.

    Article  Google Scholar 

  11. Lee DW, Stetler-Stevenson M, Yuan CM, Yuan CM, Fry TJ, Shah NN et al. Safety and response of incorporating CD19 chimeric antigen receptor T cell therapy in typical salvage regimens for children and young adults with acute lymphoblastic leukemia. Blood 2015; 126: 684.

    Article  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: 224ra25.

    Article  Google Scholar 

  13. Lujia Dong, Lung-Ji Chang, Zhiyong Gao, Dao-Pei Lu, Jian-Ping Zhang, Jing-Bo Wang et al. Chimeric antigen receptor 4SCAR19-modified T cells in acute lymphoid leukemia: a phase II multi-center clinical trial in China. Blood 2015; 126: 3774.

    Google Scholar 

  14. Park JH, Riviere I, Wang X, Bernal Y, Purdon T, Halton E et al. Implications of minimal residual disease negative complete remission (MRD-CR) and allogeneic stem cell transplant on safety and clinical outcome of CD19-targeted 19-28z CAR modified T cells in adult pts with relapsed, refractory B-cell ALL. Blood 2015; 126: 682.

    Google Scholar 

  15. Kebriaei P, Huls H, Singh H, Olivares S, Figliola M, Maiti S et al. Adoptive therapy using Sleeping Beauty gene transfer system and artificial antigen presenting cells to manufacture T cells expressing CD19-specific chimeric antigen receptor. Blood 2014; 124: 311.

    Google Scholar 

  16. Brentjens RJ, Davila ML, Riviere I, Park JH, Wang X, Cowell LG et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5: 177ra38.

    Article  Google Scholar 

  17. Park JH, Riviere I, Wang X, Purdon T, Sadelain M, Brentjens RJ . Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed B-ALL. J Clin Oncol 2016; 34: (abstract 7003).

    Article  Google Scholar 

  18. 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: 2123–2138.

    Article  Google Scholar 

  19. Frey NV, Shaw PA, Hexner EO, Gill S, Marcucci K, Luger SM et al. Optimizing chimeric antigen receptor (CAR)T cell therapy for adult patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL). J Clin Oncol 2016; 34: (abstract 7002).

    Article  Google Scholar 

  20. Pan J, Zhang Y, Zhao YL, Yang JF, Zhang JP, Liu HX et al. Impact of clinical factors on outcome of leukemia patients with TLS-ERG fusion gene. Leuk Lymphoma 2016; 22: 1–9.

    Google Scholar 

  21. Chang AH, Stephan MT, Sadelain M . Stem cell–derived erythroid cells mediate long-term systemic protein delivery. Nat Biotechnol 2006; 24: 1017–1021.

    Article  CAS  Google Scholar 

  22. Stephan MT, Ponomarev V, Brentjens RJ, Chang AH, Dobrenkov KV, Heller G et al. T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 2007; 13: 1440–1449.

    Article  CAS  Google Scholar 

  23. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124: 188–195.

    Article  CAS  Google Scholar 

  24. US Department of Health and Human Services. Common terminology criteria for adverse events. V4. 03 2010.[EB/OL]. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.

  25. Alvarnas JC, Brown PA, Advani A, Aoun P, Ballen KK, Barta SK et alNCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukemia, Verison 1, 2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/all.pdf.

  26. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3: 95ra73.

    Article  CAS  Google Scholar 

  27. Grupp SA, Maude SL, Shaw PA, Aplenc R, Barrett DM, Callahan C et al. Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019). Blood 2015; 126: 681.

    Google Scholar 

  28. Kenderian SS, Porter DL, Gill S . Chimeric antigen receptor T cells and hematopoietic cell transplantation: how not to put the CART before the horse. Biol Blood Marrow Transplant 2016; 23: 235–246.

    Article  Google Scholar 

  29. 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: 517–528.

    Article  CAS  Google Scholar 

  30. Turtle CJ, Hanafi LA, 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.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Hongxing Liu, Hui Wang, Tong Wang from Pathology & Laboratory Medicine Division in Hebei Yanda Lu Daopei Hospital for technical assistance. Yanli Zhao from Department of Bone Marrow Transplantation of Hebei Yanda Lu Daopei Hospital for providing clinical consultation. This work was supported by National Key Basic Research Program of China (973 Program Grant No. 2014CB965000, 2014CB965001 and 2014CB965002) and National Natural Science Foundation of China (81272325).

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Correspondence to A H Chang or C R Tong.

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AHC is also a founding member of Shanghai YaKe Biotechnology Ltd., a biotechnology company focused on research and development of tumor cell immunotherapy. YZ and SL are also employees of Shanghai YaKe Biotechnoloy Ltd. The remaining authors declare no conflict of interest.

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Pan, J., Yang, J., Deng, B. et al. High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia 31, 2587–2593 (2017). https://doi.org/10.1038/leu.2017.145

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