Autologous CD19-directed chimeric antigen receptor-T cell is an effective and safe treatment to refractory or relapsed diffuse large B-cell lymphoma

Abstract

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Chimeric antigen receptor (CAR) modified T cells targeting CD19 hold great promise to improve the complete response rates of DLBCL patients compared with conventional therapies. Here, we conducted a clinical trial to evaluate the efficacy and safety of CAR-T cells. Five patients with relapsed or refractory DLBCL were treated with autologous T cells expressing the 19-41BBz chimeric antigen receptor (CAR) specifically targeted the CD19 antigen (IM19 CAR-T). The development of cytokine release syndrome (CRS) was observed. And the efficacy of IM19 CAR-T cell treatment was measured with positron emission tomography (PET)–computed tomography (CT). Of the four patients evaluable for response, two obtained complete responses (CRs), one obtained partial response (PR), and one had stable disease (SD). Remarkably, among the five patients, only one developed grade 2 CRS while the others only elicited grade 1 CRS. Additionally, the efficacy and safety of IM19 CAR-T cells were correlated with the peak blood level and persistence of CAR-T cells, as well as the immunophenotype of T-cell subsets. Overall, this study indicates the feasibility and effectiveness of IM19 CAR-T cells in the treatment of refractory or relapsed diffuse large B-cell lymphoma.

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Data availability

The dataset(s) supporting the findings of this study are included within the article.

References

  1. 1.

    Chaganti S, Illidge T, Barrington S, Mckay P, Linton K, Cwynarski K et al. Guidelines for the management of diffuse large B-cell lymphoma. Br J Haematol. 2016; 174:43–56.

    Article  Google Scholar 

  2. 2.

    Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125:22.

    CAS  Article  Google Scholar 

  3. 3.

    Ng AK. Diffuse large B-cell lymphoma. Semin Radiat Oncol. 2007;17:169–75.

    Article  Google Scholar 

  4. 4.

    Seshadri T, Stakiw J, Pintilie M, Keating A, Crump M, Kuruvilla J. Utility of subsequent conventional dose chemotherapy in relapsed/refractory transplant-eligible patients with diffuse large B-cell lymphoma failing platinum-based salvage chemotherapy. Hematology. 2008;13:261–6.

    CAS  Article  Google Scholar 

  5. 5.

    Crump M, Neelapu SS, Farooq U, Van DNE, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;16:S101–S101.

    Google Scholar 

  6. 6.

    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.

    CAS  Article  Google Scholar 

  7. 7.

    Kochenderfer JN, Dudley ME, Kassim SH, Somerville RPT, 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;33:540–9.

    CAS  Article  Google Scholar 

  8. 8.

    Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K et al. Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129:3322–31.

  9. 9.

    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;6:224ra25–224ra25.

    Article  Google Scholar 

  10. 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. New Engl J Med. 2013;368:1509.

    CAS  Article  Google Scholar 

  11. 11.

    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. 2012;119:2709–20.

    CAS  Article  Google Scholar 

  12. 12.

    Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Müeller SP, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the international conference on malignant lymphomas imaging working group. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32:3048–58.

    Article  Google Scholar 

  13. 13.

    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;124:188–95.

    CAS  Article  Google Scholar 

  14. 14.

    Yip A, Webster RM. The market for chimeric antigen receptor T cell therapies. Nat Rev Drug Discov. 2018;​17:161–62.

    CAS  Article  Google Scholar 

  15. 15.

    Turtle CJ, Hanafi L-A, 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 Investig. 2016;126:2123–38.

    Article  Google Scholar 

  16. 16.

    Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nat Rev Cancer. 2012;12:671–84.

    CAS  Article  Google Scholar 

  17. 17.

    Klebanoff CA, Scott CD, Leonardi AJ, Yamamoto TN, Cruz AC, Ouyang C, et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J Clin Investig. 2016;126:318.

    Article  Google Scholar 

  18. 18.

    Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who’s who of T-cell differentiation: human memory T-cell subsets. Eur J Immunol. 2013;43:2797.

    CAS  Article  Google Scholar 

  19. 19.

    Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8 + T cells. J Clin Investig. 2005;115:1616.

    CAS  Article  Google Scholar 

  20. 20.

    Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8|[plus]| and CD4|[plus]| subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30:492.

    CAS  Article  Google Scholar 

  21. 21.

    Gattinoni L, Lugli E, Ji Y, Pos Z. A human memory T cell subset with stem cell-like properties. Nat Med. 2011;17:1290.

    CAS  Article  Google Scholar 

  22. 22.

    Klebanoff CA, Gattinoni L, Torabiparizi P, Kerstann K, Cardones AR, Finkelstein SE, et al. Central memory self/tumor-reactive CD8 + T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA. 2005;102:9571–6.

    CAS  Article  Google Scholar 

  23. 23.

    Sabatino M, Hu J, Sommariva M, Gautam S, Fellowes V, Hocker JD, et al. Generation of clinical-grade CD19-specific CAR-modified CD8 + memory stem cells for the treatment of human B-cell malignancies. Blood. 2016;128:519.

    CAS  Article  Google Scholar 

  24. 24.

    Lee DW, Kochenderfer JN, Stetlerstevenson 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.

    CAS  Article  Google Scholar 

  25. 25.

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

    Article  Google Scholar 

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Acknowledgements

This work was supported by Beijing Natural Science Foundation (7132183), China Health Promotion Foundation (CHPF-zlkysx-001), Key project of Peking University Third Hospital (BYSY2015004), Zhongguancun Frontier Reserve Project, Beijing Science and Technology SME Promotion Project, Beijing Science and Technology Rising Star Project and Beijing Eagle Talent Project. CAR-T cells in this study were provided by Beijing Immunochina Medical Science & Technology Co., Ltd. The clinical trial in this study was also sponsored by Beijing Immunochina Medical Science & Technology Co., Ltd.

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Contributions

JHM, QFF, LXA, and HT conceived and designed the study; BF, WW, HK, YP, DF, WJ, and JHM performed the clinical examination; JHM, BF, WW, QFF, LXA, HT, and LGH analyzed and interpreted the data; QFF, LXA, and HT designed the CAR and prepared the CAR-T cell product; HT, LGH, BF, and WW wrote the paper. All authors read and approved the final paper.

Corresponding author

Correspondence to Hongmei Jing.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

This study was performed in accordance with the Declaration of Helsinki and approved by the Peking University Third Hospital Institutional Review Board. All patients enrolled in this trial gave written informed consent after a discussion of the possible risks and adverse effects of the therapy.

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Trial registration: NCT03344705, Registered November 14, 2017, Prospective clinical trial. https://www.clinicaltrials.gov/ct2/show/NCT03344705?term=immunochina&rank=1

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Bao, F., Wan, W., He, T. et al. Autologous CD19-directed chimeric antigen receptor-T cell is an effective and safe treatment to refractory or relapsed diffuse large B-cell lymphoma. Cancer Gene Ther 26, 248–255 (2019). https://doi.org/10.1038/s41417-018-0073-7

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