Advertisement

BioDrugs

, Volume 33, Issue 1, pp 45–60 | Cite as

Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities

  • Bhagirathbhai R. Dholaria
  • Christina A. Bachmeier
  • Frederick LockeEmail author
Review Article

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has proven to be a very effective cancer immunotherapy. Axicabtagene ciloleucel and tisagenlecleucel are the first-in-class anti-CD19 CAR-T currently available for relapsed/refractory adult large B-cell lymphoma. Tisagenlecleucel is also available for pediatric and young adult (up to age 25 years) patients with relapsed/refractory B-acute lymphoblastic leukemia. Cytokine release syndrome (CRS) and CAR-T-associated encephalopathy syndrome (neurotoxicity) are the most common adverse effects associated with CAR-T therapy. They can lead to significant morbidity and preclude widespread use of this treatment modality. Treatment-related deaths from severe CRS and cerebral edema have been reported. There is a significant heterogeneity in the side-effect profile of different CAR-T products under investigation and there is a need to develop standardized guidelines for toxicity grading and management. Here, we summarize the current literature on pathogenesis, clinical presentation, and management of CRS and neurotoxicity. The different grading systems of CRS and management protocols used in different trials have made it difficult to compare the outcomes of different CAR-T therapies. Several prevention strategies such as predictive biomarkers of CRS and neurotoxicity and modified CAR-T with ‘built-in’ safety mechanisms are being studied, with the potential to greatly expand the safety and applicability of CAR-T treatment across various malignancies.

Notes

Compliance with Ethical Standards

Funding

This work was supported by an NCI K23 award (PI- Locke, F; CA201594, NIH/NCI) and an NCI Cancer Center support grant P30 (CA076292-18S4, NIH/NCI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Frederick Locke declares being a scientific advisor to Kite (a Gilead subsidiary) and Novartis; and a consultant for Cellular BioMedicine Group. Bhagirathbhai R. Dholaria and Christina Bachmeier declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

References

  1. 1.
    Lamers CH, Klaver Y, Gratama JW, Sleijfer S, Debets R. Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells-a completed study overview. Biochem Soc Trans. 2016;44(3):951–9.CrossRefGoogle Scholar
  2. 2.
    Brocker T, Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 1995;181(5):1653–9.CrossRefGoogle Scholar
  3. 3.
    Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Investig. 2011;121(5):1822–6.CrossRefGoogle Scholar
  4. 4.
    Wang X, Riviere I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolyt. 2016;3:16015.CrossRefGoogle Scholar
  5. 5.
    June CH, Riddell SR, Schumacher TN. Adoptive cellular therapy: a race to the finish line. Sci Transl Med. 2015;7(280):280ps7.CrossRefGoogle Scholar
  6. 6.
    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.CrossRefGoogle Scholar
  7. 7.
    Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54.CrossRefGoogle Scholar
  8. 8.
    Borchmann P, Tam C, Jäger U, McGuirk J, Holte H, Waller E, et al. An updated analysis of JULIET, a global pivotal phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory diffuse large B-cell lymphoma. European Hematology Association, abstract S799; June 2018.Google Scholar
  9. 9.
    FDA approves second CAR T-cell therapy. Cancer Discov. 2018;8(1):5–6. http://cancerdiscovery.aacrjournals.org/content/8/1/5.full
  10. 10.
    Heymach J, Krilov L, Alberg A, Baxter N, Chang SM, Corcoran R, et al. Clinical Cancer advances 2018: annual report on progress against cancer from the american society of clinical oncology. J Clin Oncol. 2018;36(10):1020–44.CrossRefGoogle Scholar
  11. 11.
    First two CAR-T cell medicines recommended for approval in the European Union 2018. https://www.ema.europa.eu/en/news/first-two-car-t-cell-medicines-recommended-approval-european-union. Accessed 19 Oct 2018.
  12. 12.
    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. 2017;Sep:19.Google Scholar
  13. 13.
    Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30.CrossRefGoogle Scholar
  14. 14.
    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(2):188–95.CrossRefGoogle Scholar
  15. 15.
    Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24(6):731–8.CrossRefGoogle Scholar
  16. 16.
    Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24(6):739–48.CrossRefGoogle Scholar
  17. 17.
    Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T cell therapy. Blood. 2017;Sep:18.Google Scholar
  18. 18.
    van der Stegen SJ, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14(7):499–509.CrossRefGoogle Scholar
  19. 19.
    Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.CrossRefGoogle Scholar
  20. 20.
    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(16):1507–17.CrossRefGoogle Scholar
  21. 21.
    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 Investig. 2016;126(6):2123–38.CrossRefGoogle Scholar
  22. 22.
    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;19;6(224):224ra25.CrossRefGoogle Scholar
  23. 23.
    NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 data file. 2009; 4.0:[NCI]. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 13 Sept 2014.
  24. 24.
    Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017; https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed 22 Apr 2018.
  25. 25.
    Neelapu SS, Tummala S, Kebriaei P, Wierda W, Locke FL, Lin Y, et al. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit ‘ALL’. Nat Rev Clin Oncol. 2018;15(4):218.CrossRefGoogle Scholar
  26. 26.
    Porter DL, Hwang W-T, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139–303ra139.Google Scholar
  27. 27.
    Porter D, Frey N, Wood PA, Weng Y, Grupp SA. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol. 2018;11(1):35.CrossRefGoogle Scholar
  28. 28.
    CAR-T toxicity rating system to be finalized by ASBMT by year-end—Drug Development Technology. https://www.drugdevelopment-technology.com/comment/car-t-toxicity-rating-system-finalized-asbmt-year-end/. Accessed 11 Sept 2018.
  29. 29.
    Schuster SJBM, Tam CS. Primary analysis of JULIET: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2017;130(suppl 1).Google Scholar
  30. 30.
    Davila ML, Sadelain M. Biology and clinical application of CAR T cells for B cell malignancies. Int J Hematol. 2016;104(1):6–17.CrossRefGoogle Scholar
  31. 31.
    Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2017;Aug:31.CrossRefGoogle Scholar
  32. 32.
    Center for Drug Evaluation and Research. Approved Drugs—FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm574154.htm. Accessed 21 Nov 2018.
  33. 33.
    Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Jacobson CA, Braunschweig I, et al. Preliminary results of prophylactic tocilizumab after axicabtageneciloleucel (axi-cel; KTE-C19) treatment for patients with refractory, aggressive non-hodgkin lymphoma (NHL). Blood. 2017;130(Suppl 1):1547.Google Scholar
  34. 34.
    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(6):664–79.CrossRefGoogle Scholar
  35. 35.
    van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fossa A, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014;15(9):966–74.CrossRefGoogle Scholar
  36. 36.
    Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–64.CrossRefGoogle Scholar
  37. 37.
    Brentjens RJ, Davila ML, Riviere I, Park J, 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;20(177):177ra38.Google Scholar
  38. 38.
    Teachey DT, Bishop MR, Maloney DG, Grupp SA. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. Nat Rev Clin Oncol. 2018;15(4):218.CrossRefGoogle Scholar
  39. 39.
    Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–19.CrossRefGoogle Scholar
  40. 40.
    DeAngelo D, Ghobadi A, Park J, Dinner S, Mannis G, Lunning M, et al. Clinical outcomes for the phase 2, single-arm, multicenter trial of JCAR015 in adult B-ALL (ROCKET Study). 32nd annual meeting and pre-conference programs of the Society for Immunotherapy of Cancer (SITC 2017): part one. J Immunother Cancer. 2017;5(2):86.Google Scholar
  41. 41.
    Santomasso B, Park JH, Riviere I, Mead E, Halton E, Diamonte C, et al. Biomarkers associated with neurotoxicity in adult patients with relapsed or refractory B-ALL (R/R B-ALL) treated with CD19 CAR T cells. J Clin Oncol. 2017;35(15_suppl):3019.Google Scholar
  42. 42.
    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.CrossRefGoogle Scholar
  43. 43.
    Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59.CrossRefGoogle Scholar
  44. 44.
  45. 45.
    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. J Clin Oncol. 2018;36(15_suppl):7505.Google Scholar
  46. 46.
    Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, et al. Clinical and biologic correlates of neurotoxicity associated with CAR T cell therapy in patients with B-cell Acute lymphoblastic leukemia (B-ALL). Cancer Discov. 2018;8(8):958–71.CrossRefGoogle Scholar
  47. 47.
    Taraseviciute A, Tkachev V, Ponce R, Turtle CJ, Snyder JM, Liggitt HD, et al. Chimeric antigen receptor T cell-mediated neurotoxicity in nonhuman primates. Cancer Discov. 2018;8(6):750–63.CrossRefGoogle Scholar
  48. 48.
    Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295–306.CrossRefGoogle Scholar
  49. 49.
    Higgins SJ, Purcell LA, Silver KL, Tran V, Crowley V, Hawkes M, et al. Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Sci Transl Med. 2016;28;8(358):358ra128.CrossRefGoogle Scholar
  50. 50.
    Kochenderfer JN, Somerville RPT, 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. 2017;35(16):1803–13.CrossRefGoogle Scholar
  51. 51.
    Turtle CJ, Hay KA, Juliane G, Hanafi L-A, Li D, Chaney C, et al. Biomarkers of Cytokine Release Syndrome and Neurotoxicity after CD19 CAR-T cells and mitigation of toxicity by cell dose. Blood. 2016;128(22):1852.Google Scholar
  52. 52.
    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 (London, England). 2015;385(9967):517–28.CrossRefGoogle Scholar
  53. 53.
    Hu Y, Sun J, Wu Z, Yu J, Cui Q, Pu C, et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol Engl. 2016;9(1):70.CrossRefGoogle Scholar
  54. 54.
    Prudent V, Breitbart WS. Chimeric antigen receptor T-cell neuropsychiatric toxicity in acute lymphoblastic leukemia. Palliat Support Care. 2017;15(4):499–503.CrossRefGoogle Scholar
  55. 55.
    Raje NS, Berdeja JG, Lin Y, Munshi N, Siegel BA, Liedtke M, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007).Google Scholar
  56. 56.
    Pangman VC, Sloan J, Guse L. An examination of psychometric properties of the mini-mental state examination and the standardized mini-mental state examination: implications for clinical practice. ANR. 2000;13(4):209–13.Google Scholar
  57. 57.
    Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet (London, England). 1974;2(7872):81–4.CrossRefGoogle Scholar
  58. 58.
    Cohen AD, Garfall AL, Stadtmauer EA, Lacey SF, Lancaster E, Vogl DT, et al. Safety and efficacy of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) with cyclophosphamide conditioning for refractory multiple myeloma (MM). Blood. 2017;130(Suppl 1):505.Google Scholar
  59. 59.
    Locke F, Ghobadi A, Lekakis LJ, Miklos DB, Jacobson CA, Jacobsen ED, et al. Outcomes by prior lines of therapy (LoT) in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B cell lymphoma. J Clin Oncol. 2018;36(no. 15_suppl):3039.Google Scholar
  60. 60.
    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(1):285–95.CrossRefGoogle Scholar
  61. 61.
    Gardner R, Leger KJ, Annesley CE, Summers C, Rivers J, Gust J, et al. Decreased rates of severe CRS seen with early intervention strategies for CD19 CAR-T cell toxicity management. Blood. 2016;128(22):586.Google Scholar
  62. 62.
    Chen F, Teachey DT, Pequignot E, Frey N, Porter D, Maude SL, et al. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods. 2016;434:1–8.CrossRefGoogle Scholar
  63. 63.
    Park JH, Santomasso B, Riviere I, Senechal B, Wang X, Purdon T, et al. Baseline and early post-treatment clinical and laboratory factors associated with severe neurotoxicity following 19-28z CAR T cells in adult patients with relapsed B-ALL. J Clin Oncol. 2017;35(15_suppl):7024.Google Scholar
  64. 64.
    Ghorashian S, Kramer AM, Albon SJ, Wright G, Castro F, Popova B, et al. A Novel Low affinity CD19CAR results in durable disease remissions and prolonged CAR T cell persistence without severe CRS or neurotoxicity in patients with paediatric ALL. Blood. 2017;130(Suppl 1):806.Google Scholar
  65. 65.
    Watanabe K, Terakura S, Uchiyama S, Martens AC, Meerten TV, Kiyoi H, et al. Excessively high-affinity single-chain fragment variable region in a chimeric antigen receptor can counteract T-cell proliferation. Blood. 2014;124(21):4799.Google Scholar
  66. 66.
    Park S, Shevlin E, Vedvyas Y, Zaman M, Hsu YS, Min IM, et al. Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Sci Rep. 2017;7(1):14366.CrossRefGoogle Scholar
  67. 67.
    Schmid DA, Irving MB, Posevitz V, Hebeisen M, Posevitz-Fejfar A, Sarria JC, et al. Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol. 2010;184(9):4936–46.CrossRefGoogle Scholar
  68. 68.
    Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent anti-tumor activity. Cancer Res. 2015;75(17):3505–18.CrossRefGoogle Scholar
  69. 69.
    Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7.CrossRefGoogle Scholar
  70. 70.
    Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D, Theriault K, et al. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med. 2018;24(7):939–46.CrossRefGoogle Scholar
  71. 71.
    Zhou X, Brenner MK. Improving the safety of T-Cell therapies using an inducible caspase-9 gene. Exp Hematol. 2016;44(11):1013–9.CrossRefGoogle Scholar
  72. 72.
    Casucci M, Falcone L, Camisa B, Norelli M, Porcellini S, Stornaiuolo A, et al. Extracellular NGFR spacers allow efficient tracking and enrichment of fully functional CAR-T cells co-expressing a suicide gene. Front Immunol. 2018;9:507.CrossRefGoogle Scholar
  73. 73.
    Minagawa K, Jamil MO, Al-Obaidi M, Pereboeva L, Salzman D, Erba HP, et al. In vitro pre-clinical validation of suicide gene modified anti-CD33 redirected chimeric antigen receptor T-cells for acute myeloid leukemia. PLoS One. 2016;11(12):e0166891.CrossRefGoogle Scholar
  74. 74.
    Tasian SK, Kenderian SS, Shen F, Ruella M, Shestova O, Kozlowski M, et al. Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood. 2017;129(17):2395–407.CrossRefGoogle Scholar
  75. 75.
    Qasim W, Ciocarlie O, Adams S, Inglott S, Murphy C, Rivat C, et al. Preliminary results of UCART19, an allogeneic anti-CD19 CAR T-cell product in a first-in-human trial (PALL) in pediatric patients with CD19 + relapsed/refractory B-cell acute lymphoblastic leukemia. Blood. 2017;130(Suppl 1):1271.Google Scholar
  76. 76.
    Sakemura R, Terakura S, Watanabe K, Julamanee J, Takagi E, Miyao K, et al. A tet-on inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol Res. 2016;4(8):658–68.CrossRefGoogle Scholar
  77. 77.
    Ma JS, Kim JY, Kazane SA, Choi SH, Yun HY, Kim MS, et al. Versatile strategy for controlling the specificity and activity of engineered T cells. Proc Natl Acad Sci USA. 2016;113(4):E450–8.CrossRefGoogle Scholar
  78. 78.
    Juillerat A, Marechal A, Filhol JM, Valogne Y, Valton J, Duclert A, et al. An oxygen sensitive self-decision making engineered CAR T-cell. Sci Rep. 2017;20(7):39833.CrossRefGoogle Scholar
  79. 79.
    Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell. 2016;164(4):770–9.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Blood and Marrow Transplantation and Cellular ImmunotherapyMoffitt Cancer CenterTampaUSA
  2. 2.Department of PharmacyMoffitt Cancer CenterTampaUSA

Personalised recommendations