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Excessive activated T-cell proliferation after anti-CD19 CAR T-cell therapy

Abstract

Excessive activated T-cell proliferation was observed in vivo in one patient after an anti-CD19-chimeric antigen receptor (CAR) T-cell infusion. The patient, who had chemotherapy refractory and CD19+ diffuse large B-cell lymphoma (DLBCL), received an anti-CD19 CAR T-cell infusion following conditioning chemotherapy (fludarabine/cyclophosphamide). The lymphocyte count in the peripheral blood (PB) increased to 77 × 109/L on day 13 post infusion, and the proportion of CD8+ actived T cells was 93.06% of the lymphocytes. Then, the patient suffered from fever and hypoxaemia. Significant increases in serum cytokine, lactate dehydrogenase, aspartate aminotransferase (AST), alanine transaminase (ALT), and glutamic-oxalacetic transaminase (γ-GT) levels were observed. A high-throughput sequencing analysis for T-cell receptors (TCRs) and whole-genome sequencing were used to explore the mechanisms underlying this excessive T-cell proliferation. TCR diversity was demonstrated, but no special gene mutation was found. The patient was found to be infected with the John Cunningham polyomavirus (JCV). It cannot be ruled out the bystander activation pathway induced by JCV infections related the excessive activated T-cell proliferation. Although the clinical and laboratory data do not fully explain the reason for excessive T-cell proliferation after the anti-CD19 CAR T-cell infusion, the risk of this type of toxicity should be emphasized. This study was registered at www.clinicaltrials.gov as NCT01864889.

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References

  1. Levine BL, Miskin J, Wonnacott K, Keir C. Global manufacturing of CAR T cell therapy. Mol Ther Methods Clin Dev. 2017;4:92–101.

    Article  CAS  Google Scholar 

  2. 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  Google Scholar 

  3. Oluwole OO, Davila ML. At the bedside: clinical review of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies. J Leukoc Biol. 2016;100:1265–72.

    Article  CAS  Google Scholar 

  4. Ramos CA, Heslop HE, Brenner MK. CAR-T cell therapy for lymphoma. Annu Rev Med. 2016;67:165–83.

    Article  CAS  Google Scholar 

  5. Dai HR, Zhang WY, Li SX, Han QW, Guo YL, 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 

  6. Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, et al. Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol. 2014;155:160–75.

    Article  CAS  Google Scholar 

  7. Cai B, Guo M, Wang Y, Zhang Y, Yang J, Guo Y, et al. Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia. J Hematol Oncol. 2016;9:131.

    Article  Google Scholar 

  8. 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 

  9. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20:119–22.

    Article  CAS  Google Scholar 

  10. Fesnak AD, June CH, Levine BL. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer. 2016;16:566–81.

    Article  CAS  Google Scholar 

  11. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126:3130–44.

    Article  Google Scholar 

  12. Ford ML, Koehn BH, Wagener ME, Jiang W, Gangappa S, Pearson TC, et al. Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation. J Exp Med. 2007;204:299–309.

    Article  CAS  Google Scholar 

  13. Varmus HE, Quintrell N, Ortiz S. Retroviruses as mutagens: insertion and excision of a nontransforming provirus alter expression of a resident transforming provirus. Cell. 1981;25:23–36.

    Article  CAS  Google Scholar 

  14. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415–9.

    Article  CAS  Google Scholar 

  15. Mani J, Wang L, Huckelhoven AG, Schmitt A, Gedvilaite A, Jin N, et al. Definition and characterization of novel HLA-*A02-restricted CD8+ T cell epitopes derived from JCV polyomavirus with clinical relevance. Oncotarget. 2017;8:2485–2500.

    PubMed  Google Scholar 

  16. Hsu C, Jones SA, Cohen CJ, Zheng Z, Kerstann K, Zhou J, et al. Cytokine-independent growth and clonal expansion of a primary human CD8+T-cell clone following retroviral transduction with the IL-15 gene. Blood. 2007;109:5168–77.

    Article  CAS  Google Scholar 

  17. Mani J, Jin N, Schmitt M. Cellular immunotherapy for patients with reactivation of JC and BK polyomaviruses after transplantation. Cytotherapy. 2014;16:1325–35.

    Article  CAS  Google Scholar 

  18. Tough DF, Borrow P, Sprent J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science. 1996;272:1947–50.

    Article  CAS  Google Scholar 

  19. Andreasen SO, Christensen JP, Marker O, Thomsen AR. Virus-induced non-specific signals cause cell cycle progression of primed CD8 (+) T cells but do not induce cell differentiation. Int Immunol. 1999;11:1463–73.

    Article  CAS  Google Scholar 

  20. Nie J, Zhang Y, Li X, Chen M, Liu C, Han W. DNA demethylating agent decitabine broadens the peripheral T cell receptor repertoire. Oncotarget. 2016;7:37882–92.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 81402566, 81472612), the grants the Science and Technology Planning Project of Beijing City (No. Z151100003915076 to W.-D.H.) and the National Key Research and Development Program of China (No. 2016YFC1303501 and 2016YFC1303504 to W.-D.H.).

Author contributions

W.-Y.Z., Y.L. and Z.-Q.W. designed and performed the in vitro experiment, analyzed the data, and wrote the manuscript; J.N., G.Y.-L. and D.H.-R. performed the in vitro experiments; Q.-M.Y. and W.C.-M. ensured compliance with regulatory requirements for the clinical trial; Y.W. supervised the manufacture of cells in infusion; W.-D.H. enroled patients in the study, analyzed the data, and wrote and reviewed the manuscript.

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Correspondence to Zhi-qiang Wu or Wei-dong Han.

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Zhang, Wy., Liu, Y., Wang, Y. et al. Excessive activated T-cell proliferation after anti-CD19 CAR T-cell therapy. Gene Ther 25, 198–204 (2018). https://doi.org/10.1038/s41434-017-0001-8

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