Focused evaluation of the roles of macrophages in chimeric antigen receptor (CAR) T cell therapy associated cytokine release syndrome

Geyer MB. First CAR to pass the road test: tisagenlecleucel’s drive to FDA approval. Clin Cancer Res. 2019; 25: 1133-35.

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. 2015; 385: 517-28.

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: 2531-44.

Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018; 378: 449-59.

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.

Frey NV, Shaw PA, Hexner EO, Pequignot E, Gill S, Luger SM, et al. Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia. J Clin Oncol. 2020; 38: 415-22.

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: 2295-306.

Oved JH, Barrett DM, Teachey DT. Cellular therapy: immune-related complications. Immunol Rev. 2019; 290: 114-26.

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.

Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016; 127: 3321-30.

Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020; 383: 2255-73.

Ferrara JL, Abhyankar S, Gilliland DG. Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant Proc. 1993; 25: 1216-7.

Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013; 121: 5154-7.

McGonagle D, Sharif K, O’Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev. 2020; 19: 102537.

Cheng Z, Huo X, Dai Y, Lu X, Hylkema MN, Xu X. Elevated expression of AhR and NLRP3 link polycyclic aromatic hydrocarbon exposure to cytokine storm in preschool children. Environ Int. 2020; 139: 105720.

Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018; 6: 56.

Liu Y, Fang Y, Chen X, Wang Z, Liang X, Zhang T, et al. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci Immunol. 2020; 5: eaax7969.

Hao Z, Li R, Meng L, Han Z, Hong Z. Macrophage, the potential key mediator in CAR-T related CRS. Exp Hematol Oncol. 2020; 9: 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: 731-38.

Shi CS, Huang TH, Lin CK, Li JM, Chen MH, Tsai ML, et al. VEGF production by Ly6C+high monocytes contributes to ventilator-induced lung injury. PLoS One. 2016; 11: e0165317.

Flierl MA, Rittirsch D, Nadeau BA, Chen AJ, Sarma JV, Zetoune FS, et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature. 2007; 449: 721-5.

Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020; 20: 355-62.

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395: 1033-34.

Fields JK, Günther S, Sundberg EJ. Structural basis of IL-1 family cytokine signaling. Front Immunol. 2019; 10: 1412.

Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013; 39: 1003-18.

Mantovani A, Dinarello CA, Molgora M, Garlanda C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity. 2019; 50: 778-95.

Vallurupalli M, Berliner N. Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis. Blood. 2019; 134: 1783-86.

Huang Y, Li D, Zhang PF, Liu M, Liang X, Yang X, et al. IL-18R-dependent and independent pathways account for IL-18-enhanced antitumor ability of CAR-T cells. Faseb J. 2020; 34: 1768-82.

Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012; 11: 633-52.

Hirano S, Zhou Q, Furuyama A, Kanno S. Differential regulation of IL-1β and IL-6 release in murine macrophages. Inflammation. 2017; 40: 1933-43.

Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2019; 26: 99-114.

Parzych K, Zetterqvist AV, Wright WR, Kirkby NS, Mitchell JA, Paul-Clark MJ. Differential role of pannexin-1/ATP/P2X(7) axis in IL-1β release by human monocytes. Faseb J. 2017; 31: 2439-45.

Orlowski GM, Colbert JD, Sharma S, Bogyo M, Robertson SA, Rock KL. Multiple cathepsins promote pro-IL-1β synthesis and NLRP3-mediated IL-1β activation. J Immunol. 2015; 195: 1685-97.

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: 739-48.

Sandler RD, Tattersall RS, Schoemans H, Greco R, Badoglio M, Labopin M, 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.

Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2016; 8: 959-70.

Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020; 55: 105954.

Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity. 2019; 50: 1007-23.

Netea MG, Kullberg BJ, Verschueren I, van der Meer JW. Interleukin-18 induces production of proinflammatory cytokines in mice: no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-1beta. Eur J Immunol. 2000; 30: 3057-60.

Mauer J, Denson JL, Bruning JC. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015; 36: 92-101.

Cerqueira DM, Pereira MS, Silva AL, Cunha LD, Zamboni DS. Caspase-1 but not caspase-11 is required for NLRC4-mediated pyroptosis and restriction of infection by flagellated legionella species in mouse macrophages and in vivo. J Immunol. 2015; 195: 2303-11.

Aizawa E, Karasawa T, Watanabe S, Komada T, Kimura H, Kamata R, et al. GSDME-Dependent incomplete pyroptosis permits selective IL-1α release under caspase-1 inhibition. iScience. 2020; 23:101070.

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.

Singh N, Hofmann TJ, Gershenson Z, Levine BL, Grupp SA, Teachey DT, et al. Monocyte lineage-derived IL-6 does not affect chimeric antigen receptor T-cell function. Cytotherapy. 2017; 19: 867-80.

Wei J, Liu Y, Wang C, Zhang Y, Tong C, Dai G, et al. The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma. Signal Transduct Target Ther. 2020; 5: 134.

Gomez-Salinero JM, Rafii S. Plasmin regulation of acute cytokine storm. Blood. 2017; 130: 5-6.

Karki R, Sharma BR, Tuladhar S, Williams EP, Zalduondo L, Samir P, et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell. 2020; 184: 149-68.

Wang W, Ye L, Ye L, Li B, Gao B, Zeng Y, et al. Up-regulation of IL-6 and TNF-alpha induced by SARS-coronavirus spike protein in murine macrophages via NF-kappaB pathway. Virus Res. 2007; 128: 1-8.

Hijano DR, Vu LD, Kauvar LM, Tripp RA, Polack FP, Cormier SA. Role of type Ⅰ interferon (IFN) in the respiratory syncytial virus (RSV) immune response and disease severity. Front Immunol. 2019; 10: 566.

Kim YI, Kim SG, Kim SM, Kim EH, Park SJ, Yu KM, et al. Infection and rapid transmission of SARS-CoV-2 in ferrets. Cell Host Microbe. 2020; 27: 704-09.e2.

Lee JS, Park S, Jeong HW, Ahn JY, Choi SJ, Lee H, et al. Immunophenotyping of COVID-19 and influenza highlights the role of type Ⅰ interferons in development of severe COVID-19. Science Immunology. 2020; 5: eabd1554.

Tomescu C, Tebas P, Montaner LJ. IFN-alpha augments natural killer-mediated antibody-dependent cellular cytotoxicity of HIV-1-infected autologous CD4+ T cells regardless of major histocompatibility complex class 1 downregulation. AIDS. 2017; 31: 613-22.

Kieler M, Hofmann M, Schabbauer G. More than just protein building blocks: how amino acids and related metabolic pathways fuel macrophage polarization. FEBS J. 2021; 288: 3694-714.

Becher B, Tugues S, Greter M. GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity. 2016; 45: 963-73.

Sterner RM, Sakemura R, Cox MJ, Yang N, Khadka RH, Forsman CL, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019; 133: 697-709.

Sachdeva M, Duchateau P, Depil S, Poirot L, Valton J. 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: 5430-37.

Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don’t know. Cell Res. 2006; 16: 126-33.

Vogel DY, Kooij G, Heijnen PD, Breur M, Peferoen LA, van der Valk P, et al. GM-CSF promotes migration of human monocytes across the blood brain barrier. Eur J Immunol. 2015; 45: 1808-19.

Yoshimura T. The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally? Cell Mol Immunol. 2018; 15: 335-45.

Ping D, Boekhoudt GH, Rogers EM, Boss JM. Nuclear factor-kappa B p65 mediates the assembly and activation of the TNF-responsive element of the murine monocyte chemoattractant-1 gene. J Immunol. 1999; 162: 727-34.

Zhu JF, Valente AJ, Lorenzo JA, Carnes D, Graves DT. Expression of monocyte chemoattractant protein 1 in human osteoblastic cells stimulated by proinflammatory mediators. J Bone Miner Res. 1994; 9: 1123-30.

Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S, et al. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest. 2008; 118: 560-70.

Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016; 535: 111-6.

Karnell JL, Rieder SA, Ettinger R, Kolbeck R. Targeting the CD40-CD40L pathway in autoimmune diseases: humoral immunity and beyond. Adv Drug Deliv Rev. 2019; 141: 92-103.

Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009; 229: 152-72.

Bossen C, Ingold K, Tardivel A, Bodmer JL, Gaide O, Hertig S, et al. Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human. J Biol Chem. 2006; 281: 13964-71.

Flierl MA, Rittirsch D, Nadeau BA, Sarma JV, Day DE, Lentsch AB, et al. Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response. PLoS One. 2009; 4: e4414.

Staedtke V, Bai RY, Kim K, Darvas M, Davila ML, Riggins GJ, et al. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature. 2018; 564: 273-77.

Mazodier K, Marin V, Novick D, Farnarier C, Robitail S, Schleinitz N, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood. 2005; 106: 3483-9.

Faramand R, Jain M, Staedtke V, Kotani H, Bai R, Reid K, et al. Tumor microenvironment composition and severe cytokine release syndrome (CRS) influence toxicity in patients with large B-cell lymphoma treated with axicabtagene ciloleucel. Clin Cancer Res. 2020; 26: 4823-31.

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: 664-79.

Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, 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: 958-71.

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: 439-48.

Wang N, Hu X, Cao W, Li C, Xiao Y, Cao Y, et al. Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies. Blood. 2020; 135: 17-27.

Taylor MD, Allada V, Moritz ML, Nowalk AJ, Sindhi R, Aneja RK, et al. Use of C-reactive protein and ferritin biomarkers in daily pediatric practice. Pediatr Rev. 2020; 41: 172-83.

Eloseily EM, Weiser P, Crayne CB, Haines H, Mannion ML, Stoll ML, et al. Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 2020; 72: 326-34.

Ramello MC, Benzaïd I, Kuenzi BM, Lienlaf-Moreno M, Kandell WM, Santiago DN, et al. An immunoproteomic approach to characterize the CAR interactome and signalosome. Sci Signal. 2019; 12: eaap9777.

Lee YG, Chu H, Lu Y, Leamon CP, Srinivasarao M, Putt KS, et al. Regulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters. Nat Commun. 2019; 10: 2681.

Ghorashian S, Kramer AM, Onuoha S, Wright G, Bartram J, Richardson R, et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019; 25: 1408-14.

Lu P, Lu XA, Zhang X, Xiong M, He T, Zhang J, et al. Which is better in CD19 CAR-T treatment of r/r B-ALL, CD28 or 4-1BB? A parallel trial under the same manufacturing process. J Clin Oncol. 2018; 36: 3041-41.

Fried S, Avigdor A, Bielorai B, Meir A, Besser MJ, Schachter J, et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant. 2019; 54: 1643-50.

Liu S, Deng B, Yin Z, Pan J, Lin Y, Ling 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: 15.

Hu Y, Wu Z, Luo Y, Shi J, Yu J, Pu C, et al. Potent anti-leukemia activities of chimeric antigen receptor-modified T cells against CD19 in Chinese patients with relapsed/refractory acute lymphocytic leukemia. Clin Cancer Res. 2017; 23: 3297-306.

Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018; 23: 943-47.

Topp MS, Gökbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015; 16: 57-66.

Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012; 8: 1237-47.

Lamb YN, Deeks ED. Sarilumab: a review in moderate to severe rheumatoid arthritis. Drugs. 2018; 78: 929-40.

Della-Torre E, Campochiaro C, Cavalli G, de Luca G, Napolitano A, La Marca S, et al. Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study. Ann Rheum Dis. 2020; 79: 1277-85.

Johnson DH, Zobniw CM, Trinh VA, Ma J, Bassett RL, Jr., Abdel-Wahab N, et al. Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. J Immunother Cancer. 2018; 6: 103.

Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011; 11: 723-37.

Saini AS, Shenoy GN, Rath S, Bal V, George A. Inducible nitric oxide synthase is a major intermediate in signaling pathways for the survival of plasma cells. Nat Immunol. 2014; 15: 275-82.

Moorlag SJCFM, Röring RJ, Joosten LAB, Netea MG. The role of the interleukin-1 family in trained immunity. Immunol Rev. 2018; 281: 28-39.