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Toci or not toci: innovations in the diagnosis, prevention, and early management of cytokine release syndrome

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Pages 2600-2611 | Received 15 Dec 2020, Accepted 17 Apr 2021, Published online: 21 Jun 2021

References

  • Whittington MD, McQueen RB, Ollendorf DA, et al. Long-term survival and value of chimeric antigen receptor t-cell therapy for pediatric patients with relapsed or refractory leukemia. JAMA Pediatr. 2018;172(12):1161–1168.
  • Lin JK, Muffly LS, Spinner MA, et al. Cost effectiveness of chimeric antigen receptor T-cell Therapy in multiply relapsed or refractory adult large B-cell lymphoma. J Clin Oncol. 2019;37(24):2105–2119.
  • Sarkar RR, Gloude NJ, Schiff D, et al. Cost-effectiveness of chimeric antigen receptor T-Cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. J Natl Cancer Inst. 2019;111(7):719–726.
  • Ma Q, Zhang J, O’Brien E, et al. Tisagenlecleucel versus historical standard therapies for pediatric relapsed/refractory acute lymphoblastic leukemia. J Comp Eff Res. 2020;9(12):849–860.
  • Purdum A, Johnson J, Bonagura A, et al. The first retrospective commercial claims-based analysis of CAR T Treated patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). Blood. 2020;136(Supplement 1):31–31.
  • Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62.
  • Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–638.
  • Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 2019;34:45–55.
  • Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517.
  • Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377(26):2531–2544.
  • Park JH, Riviere I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–459.
  • Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–448.
  • Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56.
  • Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–1737.
  • Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. The Lancet. 2020;396(10254):839–852.
  • Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331–1342.
  • Rosenbaum L. Tragedy, perseverance, and chance — The Story of CAR-T Therapy. N Engl J Med. 2017;377(14):1313–1314.
  • Yañez L, Sanchez-Escamilla M, Perales MA. CAR T cell toxicity: current management and future directions. Hemasphere. 2019;3(2):e186.
  • Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177–138.
  • Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224–225.
  • Hay KA, Hanafi LA, Li D, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295–2306.
  • Sheth VS, Gauthier J. Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. Bone Marrow Transplant. 2021;56(3):552–566.
  • Siddiqi T, Abramson JS, Li D, et al. Patient characteristics and pre-infusion biomarkers of inflammation correlate with clinical outcomes after treatment with the defined composition, CD19-targeted CAR T cell product. JCAR017. Blood. 2017;130(Suppl_1):193.
  • Wang J, Hu Y, Yang S, et al. Role of fluorodeoxyglucose positron emission tomography/computed tomography in predicting the adverse effects of chimeric antigen receptor T cell therapy in patients with non-hodgkin lymphoma. Biol Blood Marrow Transplant. 2019;25(6):1092–1098.
  • Turtle CJ, Hanafi LA, Berger C, 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(355):355ra116.
  • Spiegel JY, Sahaf B, Hossain N, et al. Elevated Axicabtagene Ciloleucel (CAR-19) expansion by immunophenotyping is associated with toxicity in diffuse large B-cell lymphoma. Blood. 2018;132(Supplement 1):576–576.
  • Frey NV, Shaw PA, Hexner EO, et al. Optimizing chimeric antigen receptor t-cell therapy for adults with acute lymphoblastic leukemia. J Clin Oncol. 2019;38:415–422.
  • Frey NV, Gill S, Hexner EO, et al. Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified t cells in relapsed chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2862–2871.
  • Munshi NC, Anderson LD, Jr., Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705–716.
  • Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322–3331.
  • Mailankody S, Jakubowiak AJ, Htut M, et al. Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011). J Clin Oncol. 2020;38(15_suppl):8504–8504.
  • Singh N, Hofmann TJ, Gershenson Z, et al. Monocyte lineage-derived IL-6 does not affect chimeric antigen receptor T-cell function. Cytotherapy. 2017;19(7):867–880.
  • Norelli M, Camisa B, Barbiera G, 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):739–748.
  • Giavridis T, van der Stegen SJC, Eyquem J, et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24(6):731–738.
  • Kang L, Tang X, Zhang J, et al. Interleukin-6-knockdown of chimeric antigen receptor-modified T cells significantly reduces IL-6 release from monocytes. Exp Hematol Oncol. 2020;9:11.
  • Alizadeh D, Wong RA, Gholamin S, et al. IFN gamma is critical for CAR T cell mediated myeloid activation and induction of endogenous immunity. Cancer Discov. 2021.
  • Staedtke V, Bai RY, Kim K, et al. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature. 2018;564(7735):273–277.
  • Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies. Blood. 2020;136(8):925–935.
  • Oluwole OO, Jansen JP, Lin VW, et al. Comparing efficacy, safety, and preinfusion period of axicabtagene ciloleucel versus tisagenlecleucel in relapsed/refractory large B cell lymphoma. Biol Blood Marrow Transplant. 2020;26(9):1581–1588.
  • Maloney DG, Kuruvilla J, Fox CP, et al. Matching-Adjusted Indirect Comparison (MAIC) of Lisocabtagene Maraleucel (liso-cel) Vs Axicabtagene Ciloleucel (axi-cel) and Tisagenlecleucel in Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL). Blood. 2020;136(Supplement 1):18–19.
  • Mian A, Wei W, Hill BT, et al. Resource utilization and factors prolonging hospitalization for patients with refractory and relapsed large B-cell lymphoma receiving tisagenlecleucel versus axicabtagene ciloleucel. Transpl Cell Ther. 2021;27(3):S307.
  • Komanduri KV. Chimeric antigen receptor T-cell therapy in the management of relapsed non-hodgkin lymphoma. J Clin Oncol. 2021;39(5):476–486.
  • Costello CL, Cohen AD, Patel KK, et al. Phase 1/2 study of the safety and response of P-BCMA-101 CAR-T Cells in patients with relapsed/refractory (r/r) multiple myeloma (MM) (PRIME) with novel therapeutic strategies. Blood. 2020;136(Supplement 1):29–30.
  • Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of Ciltacabtagene Autoleucel, a B-Cell maturation antigen-directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):22–25.
  • Jacobson CA, Hunter BD, Redd R, et al. Axicabtagene Ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J Clin Oncol. 2020;38(27):3095–3106.
  • Sandler RD, Tattersall RS, Schoemans H, et al. Diagnosis and management of secondary HLH/MAS following HSCT and CAR-T cell therapy in adults; a review of the literature and a survey of practice within EBMT centres on behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP). Front Immunol. 2020;11:524.
  • Luo H, Wang N, Huang L, et al. Inflammatory signatures for quick diagnosis of life-threatening infection during the CAR T-cell therapy. J Immunother Cancer. 2019;7(1):271.
  • Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discovery. 2016;6(6):664–679.
  • Diorio C, Shaw PA, Pequignot E, et al. Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children. Blood Adv. 2020;4(20):5174–5183.
  • Maakaron J, Penza S, El Boghdadly Z, et al. Procalcitonin as a potential biomarker for differentiating bacterial infectious fevers from cytokine release syndrome. Blood. 2018;132(Supplement 1):4216–4216. _
  • Locke FL, Rossi JM, Neelapu SS, et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(19):4898–4911.
  • Faramand R, Jain M, Staedtke V, et al. Tumor microenvironment composition and severe Cytokine Release Syndrome (CRS) influence toxicity in patients with large B-cell lymphoma treated with axicabtagene ciloleucel. Clinical Cancer Research. 2020;26(18):4823–4831.
  • Tedesco VE, Mohan C. Biomarkers for predicting cytokine release syndrome following CD19-targeted CAR T Cell therapy. J Immunol. 2021;206(7):1561–1568.
  • Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–195.
  • Guha A, Addison D, Jain P, et al. Cardiovascular events associated with chimeric antigen receptor T cell therapy: cross-sectional FDA adverse events reporting system analysis. Biol Blood Marrow Transplant. 2020;26(12):2211–2216.
  • Wudhikarn K, Pennisi M, Garcia-Recio M, et al. DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality. Blood Adv. 2020;4(13):3024–3033.
  • Jain T, Knezevic A, Pennisi M, et al. Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies. Blood Adv. 2020;4(15):3776–3787.
  • Fried S, Avigdor A, Bielorai B, et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant. 2019;54(10):1643–1650.
  • Harris AH, Hohmann S, Dolan C. Real-world quality and cost burden of cytokine release syndrome requiring tocilizumab or steroids during CAR-T infusion encounter. Biol Blood Marrow Transpl. 2020;26(3):S312.
  • Siddiqi T, Garcia J, Dehner C, et al. Estimation of the resource utilization and costs of cytokine release syndrome observed in the transcend-NHL clinical trial: a micro-costing study. Blood. 2018;132(Supplement 1):319–319.
  • Gardner RA, Ceppi F, Rivers J, et al. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood. 2019;134(24):2149–2158.
  • Kadauke S, Myers RM, Li Y, et al. Risk-adapted preemptive tocilizumab to prevent severe cytokine release syndrome after CTL019 for pediatric B-Cell acute lymphoblastic leukemia: a prospective clinical trial. J Clin Oncol. 2021;39(8):920–930.
  • Topp MS, van Meerten T, Houot R, et al. Earlier steroid use with axicabtagene Ciloleucel (Axi-Cel) in patients with relapsed/refractory large B cell lymphoma (R/R LBCL). Biol Blood Marrow Transplant. 2020;26(3 (Suppl):S101
  • Tong C, Zhao Y, Song Y, et al. Corticosteroids do not influence the efficacy and kinetics of CAR-T cells for B-Cell acute lymphoblastic leukemia. Blood. 2019;134(Supplement_1):228–228.
  • Vercellino L, Di Blasi R, Kanoun S, et al. Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 2020;4(22):5607–5615.
  • Liu S, Deng B, Yin Z, et al. Corticosteroids do not influence the efficacy and kinetics of CAR-T cells for B-cell acute lymphoblastic leukemia. Blood Cancer J. 2020;10(2):15.
  • Oluwole OO, Bouabdallah K, Munoz J, et al. Prophylactic steroid use with Axicabtagene Ciloleucel in patients with relapsed/refractory large B-Cell lymphoma. Transpl Cell Ther. 2021;27(3):S68.
  • Strati P, Ahmed S, Furqan F, et al. Prognostic impact of corticosteroids on efficacy of chimeric antigen receptor t-cell therapy in large B-cell lymphoma. Blood. 2021.
  • Nishimoto N, Terao K, Mima T, et al. 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):3959–3964.
  • Nellan A, McCully CML, Cruz Garcia R, et al. Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques. Blood. 2018;132(6):662–666.
  • Santomasso BD, Park JH, Salloum D, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8(8):958–971.
  • Locke FL, Neelapu SS, Bartlett NL, 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(Supplement 1):1547.
  • Caimi PF, Sharma A, Rojas P, et al. CAR-T therapy for lymphoma with prophylactic tocilizumab: decreased rates of severe cytokine release syndrome without excessive neurologic toxicity. Blood. 2020;136(Supplement 1):30–31.
  • Beauvais D, Karleskind O, Loridant S, et al. Potential role of tocilizumab in severe gastrointestinal barrier damage after CAR T-cell therapy. J Microbiol Immunol Infect. 2021;54(2):327–330.
  • Neill L, Mackenzie SC, Marzolini MAV, et al. Steroid use, advanced stage disease and ≥3 lines of prior chemotherapy are associated with a higher risk of infection following CD19 CAR T-cell therapy for B-NHL: real world data from a large UK center. Blood. 2020;136(Supplement 1):20–21.
  • Frigault MJ, Nikiforow S, Mansour MK, et al. Tocilizumab not associated with increased infection risk after CAR T – Implications for COVID- 19? Blood. 2020;136(1):137–139.
  • Baird JH, Epstein DJ, Tamaresis JS, et al. Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood Adv. 2021;5(1):143–155.
  • Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen receptor–modified T-cell immunotherapy. Blood. 2018;131(1):121–130.
  • Los-Arcos I, Iacoboni G, Aguilar-Guisado M, et al. Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper. Infection. 2021;49(2):215–231.
  • Schuster SJ, Maziarz RT, Rusch ES, et al. Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial. Blood Adv. 2020;4(7):1432–1439.
  • Hari P, Nguyen A, Pelletier C, et al. Healthcare resource utilization and economic burden of cytokine release syndrome (CRS) and neurologic events (NE) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) receiving idecabtagene vicleucel (ide-cel, bb2121) in KarMMa. J Clin Oncol. 2020;38(29_suppl):61–61. (no
  • Kansagra A, Lin Y, Berdeja J, et al. Characterization of Cytokine Release Syndrome (CRS) in the KarMMa Study of Idecabtagene Vicleucel (ide-cel, bb2121) for Relapsed and Refractory Multiple Myeloma (RRMM). Transpl Cell Ther. 2021;27(3):S396–S397.
  • Banerjee R, Marsal J, Huang C, et al. Early time-to-tocilizumab after BCMA-directed CAR-T therapy in myeloma. Transpl Cell Ther. 2021.
  • Strati P, Ahmed S, Kebriaei P, et al. Clinical efficacy of anakinra to mitigate CAR T-cell therapy–associated toxicity in large B-cell lymphoma. Blood Adv. 2020;4(13):3123–3127.
  • Sterner RM, Sakemura R, Cox MJ, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019;133(7):697–709.
  • Mahmoudjafari Z, Hawks KG, Hsieh AA, et al. American society for blood and marrow transplantation pharmacy special interest group survey on chimeric antigen receptor t cell therapy administrative, logistic, and toxicity management practices in the United States. Biol Blood Marrow Transplant. 2019;25(1):26–33.
  • Gutierrez C, Brown ART, Herr MM, et al. The chimeric antigen receptor-intensive care unit (CAR-ICU) initiative: Surveying intensive care unit practices in the management of CAR T-cell associated toxicities. J Crit Care. 2020;58:58–64.
  • Ortiz-Maldonado V, Rives S, Castella M, et al. CART19-BE-01: a multicenter trial of ARI-0001 cell therapy in patients with CD19(+) relapsed/refractory malignancies. Mol Ther. 2021;29(2):636–644.
  • Gauthier J, Hirayama AV, Purushe J, et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood. 2020;135(19):1650–1660.
  • Wierda WG, Dorritie KA, Munoz J, et al. Abstract 544: Transcend CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel (liso-cel) in Combination with Ibrutinib for Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Paper presented at: American Society of Hematology 2020.
  • Chavez JC, Locke FL, Napier E, et al. Ibrutinib before apheresis may improve tisagenlecleucel manufacturing in relapsed/refractory adult diffuse large B-Cell lymphoma: initial results from a phase 1b study. Blood. 2020;136(Supplement 1):3–4.
  • Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539–2549.
  • Weber EW, Lynn RC, Sotillo E, et al. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv. 2019;3(5):711–717.
  • Mestermann K, Giavridis T, Weber J, et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019;11(499):eaau5907.
  • Amatya PN, Carter AJ, Ritchey JK, et al. Abstract 1549: The Dual PI3Kδγ Inhibitor Duvelisib Potently Inhibits IL-6 Production and Cytokine Release Syndrome (CRS) While Maintaining CAR-T Function in Vitro and In Vivo. Paper presented at: American Society of Hematology 2020.
  • Pan J, Deng B, Ling Z, et al. Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy. J Cell Mol Med. 2021;25(2):1089–1099.
  • Kenderian SS, Ruella M, Shestova O, et al. Ruxolitinib Prevents Cytokine Release Syndrome after Car T-Cell Therapy Without Impairing the Anti-Tumor Effect in a Xenograft Model. Biol Blood Marrow Transpl. 2017;23(3):S19–S20.
  • Huarte E, O'Connor RS, Parker M, et al. Prophylactic Itacitinib (INCB039110) for the Prevention of Cytokine Release Syndrome Induced By Chimeric Antigen Receptor T-Cells (CAR-T-cells). Therapy Blood. 2019;134(Supplement_1):1934–1934.
  • Huarte E, O'Connor RS, Peel MT, et al. Itacitinib (INCB039110), a JAK1 inhibitor, reduces cytokines associated with cytokine release syndrome induced by CAR T-cell therapy. Clin Cancer Res. 2020;26(23):6299–6309.
  • Cummins KD, Frey N, Nelson AM, et al. Treating Relapsed/Refractory (RR) AML with biodegradable anti- CD123 CAR modified T cells. Blood. 2017;130(Suppl 1):1359.
  • Svoboda J, Rheingold SR, Gill SI, et al. Nonviral RNA chimeric antigen receptor–modified T cells in patients with Hodgkin lymphoma. Blood. 2018;132(10):1022–1026.
  • Parayath NN, Stephan SB, Koehne AL, et al. In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo. Nat Commun. 2020;11(1):6080.
  • Urbanska K, Lynn RC, Stashwick C, et al. Targeted cancer immunotherapy via combination of designer bispecific antibody and novel gene-engineered T cells. J Transl Med. 2014;12:347.
  • Lee YG, Chu H, Lu Y, et al. Regulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters. Nat Commun. 2019;10(1):2681.
  • Lu YJ, Chu H, Wheeler LW, et al. Preclinical evaluation of bispecific adaptor molecule controlled folate receptor CAR-T cell therapy with special focus on pediatric malignancies. Front Oncol. 2019;9:151.
  • Paszkiewicz PJ, Frassle SP, Srivastava S, et al. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest. 2016;126(11):4262–4272.
  • Jan M, Scarfò I, Larson RC, et al. Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Sci Transl Med. 2021;13(575):eabb6295.
  • Foster MC, Savoldo B, Lau W, et al. Utility of safety switch to abrogate CD19.CAR T cell-associated neurotoxicity. Blood. 2021.
  • Sachdeva M, Duchateau P, Depil S, et al. Granulocyte-macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte-dependent release of key cytokine release syndrome mediators. J Biol Chem. 2019;294(14):5430–5437.
  • Tan AHJ, Vinanica N, Campana D. Chimeric antigen receptor-T cells with cytokine neutralizing capacity. Blood Adv. 2020;4(7):1419–1431.
  • Chen LY, Kang LQ, Zhou HX, et al. Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia. Transl Oncol. 2020;13(11):100838.
  • Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. New Eng J Med. 2020;382(6):545–553.
  • Lin RJ, Lobaugh SM, Pennisi M, et al. Impact and safety of chimeric antigen receptor T-cell therapy in older, vulnerable patients with relapsed/refractory large B-cell lymphoma. Haematologica. 2021;106(1):255–258.
  • Bishop MR. The benefit of CAR T cells in older patients. Blood. 2020;135(23):2020–2021.
  • Cahill KE, Leukam MJ, Riedell PA. Refining patient selection for CAR T-cell therapy in aggressive large B-cell lymphoma. Leuk Lymphoma. 2020;61(4):799–807.
  • Gajra A, Jeune-Smith Y, Kish J, et al. Perceptions of community hematologists/oncologists on barriers to chimeric antigen receptor T-cell therapy for the treatment of diffuse large B-cell lymphoma. Immunotherapy. 2020;12(10):725–732.
  • Nathan C, Jeune-Smith Y, Klinefelter P, et al. Community oncologists’ perception and adaptability to emerging chimeric antigen T-cell (CAR-T) therapy. J Clin Pathways. 2017;3(8):31–35.
  • Zhu F, Wei G, Zhang M, et al. Factors associated with costs in chimeric antigen receptor T-Cell therapy for patients with relapsed/refractory B-cell malignancies. Cell Transplant. 2020;29:096368972091943.
  • Hernandez I, Prasad V, Gellad WF. Total costs of chimeric antigen receptor T-cell immunotherapy. JAMA Oncol. 2018;4(7):994–996.
  • Simons CL, Malone D, Wang M, et al. Cost-effectiveness for KTE-X19 CAR T therapy for adult patients with relapsed/refractory mantle cell lymphoma in the United States. J Med Econ. 2021;24(1):421–431.
  • Yang Y, Hao Y, Qi CZ, et al. Estimation of total costs in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia receiving tisagenlecleucel from a U.S. hospital’s perspective. J Manag Care Spec Pharm. 2020;26(8):971–980.
  • Lyman GH, Nguyen A, Snyder S, et al. Economic evaluation of chimeric antigen receptor T-cell therapy by site of care among patients with relapsed or refractory large b-cell lymphoma. JAMA Netw Open. 2020;3(4):e202072.
  • Manz CR, Porter DL, Bekelman JE. Innovation and access at the mercy of payment policy: the future of Chimeric antigen receptor therapies. J Clin Oncol. 2019;38(5):384–387.

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