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Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms

Leukemia volume 31, pages 246–248 (2017)Cite this article

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Chimeric antigen receptor T cells (CART) hold great promise for the treatment of B-cell neoplasms as multiple clinical studies have shown high complete-response rates with anti-CD19 CART in B-cell leukemia and lymphomas.1 However, widespread clinical usage of this novel immunotherapy is limited by cytokine-release syndrome (CRS). CRS is characterized by elevated serum concentration of various cytokines (IFNγ, TNFα, IL-6 and others)2 associated with high fevers and a systemic inflammation that may lead to blood hypotension, tissue hypoxia, altered mental status, multi-organ dysfunction and, in some instances, death. Some degree of CRS is observed in the majority of responding patients, in particular the ones with high tumor burden.3 Mitigating strategies to reduce CRS frequency and severity comprise of CART19 dose reduction/fractionation and tumor cytoreduction prior to CART19 infusion.4, 5, 6, 7 Recently, a novel algorithm has been developed to predict CRS after CART therapy and to potentially start pre-emptive treatments.8 However, current practice is to reserve therapy with tocilizumab, an anti-IL-6 receptor antibody, as well as steroids for patients experiencing severe (grade 3–4) CRS, due to the concern that the pre-emptive CRS treatment could impair the anti-tumor efficacy of the infused CART cells. The management of CRS remains a key factor for extending CART19 to older and frail patients, and to increase its safety in the fit adult and pediatric cohorts.9

The Bruton’s tyrosine kinase inhibitor ibrutinib has been FDA-approved for relapsing chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) and is now extensively used in B-cell neoplasms.10, 11 Our group has recently demonstrated that the rational combination of ibrutinib with CART19 leads to enhanced anti-tumor responses in preclinical model of MCL and B-cell acute lymphoblastic leukemia (ALL).12, 13 In addition to BTK, ibrutinib has been shown to inhibit the IL-2-induced tyrosine kinase, a kinase expressed in a subset of T and NK cells.14 This inhibition could result in modulation of T-cell cytokine production by T cells, as demonstrated in murine T-cell models14 and to increase the effect of checkpoint blockade,15 together with reduction of cytokine production in NK cells.16 Having found that ibrutinib also blunted cytokine production by CART19 cells in vitro,12 we hypothesized that ibrutinib would reduce CART19-mediated CRS without impairing the anti-tumor efficacy of these cells.

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References

  1. 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: 368–384.

    Article  Google Scholar 

  2. 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. Science Trans Med 2011; 3: 95ra73.

    Article  CAS  Google Scholar 

  3. 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 

  4. Frey NV LB, Lacey SF, Grupp SA, Maude SL, Schuster SJ, Shaw P et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Am Soc Hematol 2014; ASH Meeting 2014; Abs #2296.

  5. 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 

  6. Maude SL, Barrett D, Teachey DT, Grupp SA . Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 2014; 20: 119–122.

    Article  CAS  Google Scholar 

  7. 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 Trans Med 2014; 6: 224ra225.

    Article  Google Scholar 

  8. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov 2016; 6: 664–679.

    Article  CAS  Google Scholar 

  9. 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 (suppl): abstr 7002.

    Article  Google Scholar 

  10. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.

    Article  CAS  Google Scholar 

  11. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507–516.

    Article  CAS  Google Scholar 

  12. Ruella M, Kenderian SS, Shestova O, Fraietta JA, Qayyum S, Zhang Q et al. The addition of the BTK inhibitor Ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell lymphoma. Clin Cancer Res 2016; 22: 2684–2696.

    Article  CAS  Google Scholar 

  13. Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 2016; 127: 1117–1127.

    Article  CAS  Google Scholar 

  14. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013; 122: 2539–2549.

    Article  CAS  Google Scholar 

  15. Sagiv-Barfi I, Kohrt HE, Czerwinski DK, Ng PP, Chang BY, Levy R . Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci USA 2015; 112: E966–E972.

    Article  CAS  Google Scholar 

  16. Kohrt HE, Sagiv-Barfi I, Rafiq S, Herman SE, Butchar JP, Cheney C et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 2014; 123: 1957–1960.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Fang Chen and Natalka Kengle for performing the Luminex assays. The chimeric antigen receptor used in this study was obtained under MTA from Dr Dario Campana, Dr Chihaya Imai and St Jude Children’s Research Hospital and was subsequently modified by cloning into a lentiviral vector and expressed with a eukaryotic promoter.

Author contributions

MR, SSK and SG formulated the initial ideas and planned the experiments. MR, SSK, OS, MK performed the experiments and analyzed the data. MAW provided the mantle cell lymphoma primary sample. SFL and JJM designed and performed the Luminex assays. MR wrote the manuscript; SG and CHJ edited the manuscript. All the authors reviewed and accepted the contents of the article.

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Author notes

  1. M Ruella and S S Kenderian: These two authors contributed equally to this work.

Authors and Affiliations

  1. Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    M Ruella, S S Kenderian, O Shestova, M Klichinsky, J J Melenhorst, S F Lacey, C H June & S Gill

  2. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    M Ruella, S S Kenderian, O Shestova, M Klichinsky, J J Melenhorst, M A Wasik, S F Lacey, C H June & S Gill

  3. Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    M Ruella, S S Kenderian, O Shestova, J J Melenhorst, M A Wasik, S F Lacey & C H June

  4. Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

    S S Kenderian & S Gill

  5. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    M Klichinsky

  6. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA

    C H June

  7. Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    S Gill

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  1. M Ruella
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  9. S Gill
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Corresponding author

Correspondence to S Gill.

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Competing interests

The authors work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research, Inc. MR, SSK, MAW, CHK, JJM, and SG are inventors of intellectual property licensed by the University of Pennsylvania to Novartis. This work was supported by grants from the University of Pennsylvania-Novartis Alliance (PI: CHJ and SG), the NIH (5R01CA120409 grant, PI: CHJ), the Lymphoma Research Foundation (2013-2015 MCL E/D, PI: MAW and SG), the SITC (EMD-Serono Cancer Immunotherapy Clinical Fellowship, PI: MR), the AACR (Bristol-Myers Squibb Oncology Fellowship in Clinical Cancer Research, PI: MR), the SIES-AIL (PI: MR), the NCI (K12 CA090628, PI: SSK) and the NIH (T32-GM008076 to MK).

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Ruella, M., Kenderian, S., Shestova, O. et al. Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia 31, 246–248 (2017). https://doi.org/10.1038/leu.2016.262

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