A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma

Abstract

The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

Keywords

chimeric antigen receptor T (CAR-T) cell / lymphoma / cytokine release syndrome (CRS) / immune effector cell-associated neurotoxicity syndrome (ICANS)

References

[1] WHO. WHO classification of tumours of haematopoietic and lymphoid tissue. 4th ed. Geneva: World Health Organization, 2008

[2] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69(1): 7–34

[3] Zhang Y, Tuo J, Zheng R, Zhang S, Zhang M, Li G, Yang N, Lu W, Chen W. An analysis of incidence and mortality of malignant lymphoma in China, 2009. China Cancer 2013; 22: 338–343

[4] Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992; 327(21): 1478–1484

[5] Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Fermé C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010; 116(12): 2040–2045

[6] Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, López-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N, MabThera International Trial (MInT) Group. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 2011; 12(11): 1013–1022

[7] Armitage JO, Gascoyne RD, Lunning MA, Cavalli F. Non-Hodgkin lymphoma. Lancet 2017; 390(10091): 298–310

[8] Hu Y, Wu Z, Luo Y, Shi J, Yu J, Pu C, Liang Z, Wei G, Cui Q, Sun J, Jiang J, Xie J, Tan Y, Ni W, Tu J, Wang J, Jin A, Zhang H, Cai Z, Xiao L, Huang H. 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(13): 3297–3306

[9] Mueller KT, Waldron E, Grupp SA, Levine JE, Laetsch TW, Pulsipher MA, Boyer MW, August KJ, Hamilton J, Awasthi R, Stein AM, Sickert D, Chakraborty A, Levine BL, June CH, Tomassian L, Shah SS, Leung M, Taran T, Wood PA, Maude SL. Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. Clin Cancer Res 2018; 24(24): 6175–6184

[10] Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, Raffeld M, Feldman S, Lu L, Li YF, Ngo LT, Goy A, Feldman T, Spaner DE, Wang ML, Chen CC, Kranick SM, Nath A, Nathan DA, Morton KE, Toomey MA, Rosenberg SA. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 2015; 33(6): 540–549

[11] Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak Ö, Salles G, Maziarz RT,   JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019; 380(1): 45–56

[12] Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Wiezorek JS, Navale L, Xue A, Jiang Y, Bot A, Rossi JM, Kim JJ, Go WY, Neelapu SS. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol 2019; 20(1): 31–42

[13] Campana D, Schwarz H, Imai C. 4-1BB chimeric antigen receptors. Cancer J 2014; 20(2): 134–140

[14] Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 1989; 86(24): 10024–10028

[15] Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, Nagase F, Kurosawa Y. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun 1987; 149(3): 960–968

[16] Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 1993; 90(2): 720–724

[17] Brentjens RJ, Latouche JB, Santos E, Marti F, Gong MC, Lyddane C, King PD, Larson S, Weiss M, Rivière I, Sadelain M. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 2003; 9(3): 279–286

[18] Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor. Nat Biotechnol 2002; 20(1): 70–75

[19] Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH, Geiger TL, Campana D. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 2004; 18(4): 676–684

[20] Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 2010; 116(20): 4099–4102

[21] Pulè MA, Straathof KC, Dotti G, Heslop HE, Rooney CM, Brenner MK. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther 2005; 12(5): 933–941

[22] Wang J, Jensen M, Lin Y, Sui X, Chen E, Lindgren CG, Till B, Raubitschek A, Forman SJ, Qian X, James S, Greenberg P, Riddell S, Press OW. Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther 2007; 18(8): 712–725

[23] Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, Arif S, Mather SJ, Taylor-Papadimitriou J, Burchell JM, Maher J. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol 2008; 180(7): 4901–4909

[24] Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan DF, Albelda SM, Carroll RG, Riley JL, Pastan I, June CH. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA 2009; 106(9): 3360–3365

[25] Tammana S, Huang X, Wong M, Milone MC, Ma L, Levine BL, June CH, Wagner JE, Blazar BR, Zhou X. 4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. Hum Gene Ther 2010; 21(1): 75–86

[26] Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8⁺ T cell-mediated tumor eradication. Mol Ther 2010; 18(2): 413–420

[27] Hombach AA, Chmielewski M, Rappl G, Abken H. Adoptive immunotherapy with redirected T cells produces CCR7⁻ cells that are trapped in the periphery and benefit from combined CD28-OX40 costimulation. Hum Gene Ther 2013; 24(3): 259–269

[28] Duong CP, Westwood JA, Yong CS, Murphy A, Devaud C, John LB, Darcy PK, Kershaw MH. Engineering T cell function using chimeric antigen receptors identified using a DNA library approach. PLoS One 2013; 8(5): e63037

[29] Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, Raubitschek A, Forman SJ, Greenberg PD, Riddell SR, Press OW. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 2012; 119(17): 3940–3950

[30] Chen Y, Sun C, Landoni E, Metelitsa L, Dotti G, Savoldo B. Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15. Clin Cancer Res 2019; 25(9): 2915–2924

[31] Zhao Z, Condomines M, van der Stegen SJC, Perna F, Kloss CC, Gunset G, Plotkin J, Sadelain M. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 2015; 28(4): 415–428

[32] Diaconu I, Ballard B, Zhang M, Chen Y, West J, Dotti G, Savoldo B. Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells. Mol Ther 2017; 25(3): 580–592

[33] Sakemura R, Terakura S, Watanabe K, Julamanee J, Takagi E, Miyao K, Koyama D, Goto T, Hanajiri R, Nishida T, Murata M, Kiyoi H. A Tet-On inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol Res 2016; 4(8): 658–668

[34] Zhao J, Lin Q, Song Y, Liu D. Universal CARs, universal T cells, and universal CAR T cells. J Hematol Oncol 2018; 11(1): 132

[35] Cho JH, Collins JJ, Wong WW. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 2018; 173(6): 1426–1438.e11

[36] Urbanska K, Lanitis E, Poussin M, Lynn RC, Gavin BP, Kelderman S, Yu J, Scholler N, Powell DJ Jr. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res 2012; 72(7): 1844–1852

[37] Liu D, Zhao J, Song Y. Engineering switchable and programmable universal CARs for CAR T therapy. J Hematol Oncol 2019; 12(1): 69

[38] Kim MS, Ma JS, Yun H, Cao Y, Kim JY, Chi V, Wang D, Woods A, Sherwood L, Caballero D, Gonzalez J, Schultz PG, Young TS, Kim CH. Redirection of genetically engineered CAR-T cells using bifunctional small molecules. J Am Chem Soc 2015; 137(8): 2832–2835

[39] Hung CF, Xu X, Li L, Ma Y, Jin Q, Viley A, Allen C, Natarajan P, Shivakumar R, Peshwa MV, Emens LA. Development of anti-human mesothelin-targeted chimeric antigen receptor messenger RNA-transfected peripheral blood lymphocytes for ovarian cancer therapy. Hum Gene Ther 2018; 29(5): 614–625

[40] Crossland DL, Denning WL, Ang S, Olivares S, Mi T, Switzer K, Singh H, Huls H, Gold KS, Glisson BS, Cooper LJ, Heymach JV. Antitumor activity of CD56-chimeric antigen receptor T cells in neuroblastoma and SCLC models. Oncogene 2018; 37(27): 3686–3697

[41] Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, Jena B, Dawson MJ, Kumaresan PR, Su S, Maiti S, Dai J, Moriarity B, Forget MA, Senyukov V, Orozco A, Liu T, McCarty J, Jackson RN, Moyes JS, Rondon G, Qazilbash M, Ciurea S, Alousi A, Nieto Y, Rezvani K, Marin D, Popat U, Hosing C, Shpall EJ, Kantarjian H, Keating M, Wierda W, Do KA, Largaespada DA, Lee DA, Hackett PB, Champlin RE, Cooper LJ. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest 2016; 126(9): 3363–3376

[42] Turtle CJ, Berger C, Sommermeyer D, Hanafi LA, Pender B, Robinson EM, Melville K, Budiarto TM, Steevens NN, Chaney C, Cherian S, Wood BL, Soma L, Chen X, Heimfeld S, Jensen MC, Riddell SR, Maloney DG. Anti-CD19 chimeric antigen receptor-modified T cell therapy for B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes. Blood 2015; 126(23): 184

[43] Heczey A, Louis CU, Savoldo B, Dakhova O, Durett A, Grilley B, Liu H, Wu MF, Mei Z, Gee A, Mehta B, Zhang H, Mahmood N, Tashiro H, Heslop HE, Dotti G, Rooney CM, Brenner MK. CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Mol Ther 2017; 25(9): 2214–2224

[44] Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, Heslop HE, Brenner MK, Rooney CM, Ramos CA. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood 2015; 125(25): 3905–3916

[45] Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Gooley T, Li D, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Acharya UH, Cassaday RD, Chapuis AG, Dhawale TM, Hendrie PC, Kiem HP, Lynch RC, Ramos J, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood 2019; 133(17): 1876–1887

[46] Boomer JS, Green JM. An enigmatic tail of CD28 signaling. Cold Spring Harb Perspect Biol 2010; 2(8): a002436

[47] Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 2018; 131(1): 49–57

[48] Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, Patel PR, Guedan S, Scholler J, Keith B, Snyder NW, Blair IA, Milone MC, June CH. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 2016; 44(2): 380–390

[49] Wang J, Press OW, Lindgren CG, Greenberg P, Riddell S, Qian X, Laugen C, Raubitschek A, Forman SJ, Jensen MC. Cellular immunotherapy for follicular lymphoma using genetically modified CD20-specific CD8⁺ cytotoxic T lymphocytes. Mol Ther 2004; 9(4): 577–586

[50] James SE, Orgun NN, Tedder TF, Shlomchik MJ, Jensen MC, Lin Y, Greenberg PD, Press OW. Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice. Blood 2009; 114(27): 5454–5463

[51] Zhang WY, Liu Y, Wang Y, Wang CM, Yang QM, Zhu HL, Han WD. Long-term safety and efficacy of CART-20 cells in patients with refractory or relapsed B-cell non-Hodgkin lymphoma: 5-years follow-up results of the phase I and IIa trials. Signal Transduct Target Ther 2017; 2(1): 17054

[52] Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, Dimitrov DS, Morgan RA, FitzGerald DJ, Barrett DM, Wayne AS, Mackall CL, Orentas RJ. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 2013; 121(7): 1165–1174

[53] Shalabi H, Wolters PL, Martin S, Toledo-Tamula MA, Roderick MC, Struemph K, Kane E, Yates B, Delbrook C, Mackall CL, Lee DW, Fry TJ, Shah NN. Systematic evaluation of neurotoxicity in children and young adults undergoing CD22 chimeric antigen receptor T-cell therapy. J Immunother 2018; 41(7): 350–358

[54] Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, Wolters P, Martin S, Delbrook C, Yates B, Shalabi H, Fountaine TJ, Shern JF, Majzner RG, Stroncek DF, Sabatino M, Feng Y, Dimitrov DS, Zhang L, Nguyen S, Qin H, Dropulic B, Lee DW, Mackall CL. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 2018; 24(1): 20–28

[55] Dürkop H, Latza U, Hummel M, Eitelbach F, Seed B, Stein H. Molecular cloning and expression of a new member of the nerve growth factor receptor family that is characteristic for Hodgkin’s disease. Cell 1992; 68(3): 421–427

[56] Pierce JM, Mehta A. Diagnostic, prognostic and therapeutic role of CD30 in lymphoma. Expert Rev Hematol 2017; 10(1): 29–37

[57] Horie R, Watanabe T. CD30: expression and function in health and disease. Semin Immunol 1998; 10(6): 457–470

[58] Falini B, Pileri S, Pizzolo G, Dürkop H, Flenghi L, Stirpe F, Martelli MF, Stein H. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood 1995; 85(1): 1–14

[59] Hombach A, Heuser C, Sircar R, Tillmann T, Diehl V, Pohl C, Abken H. An anti-CD30 chimeric receptor that mediates CD3-ζ-independent T-cell activation against Hodgkin’s lymphoma cells in the presence of soluble CD30. Cancer Res 1998; 58(6): 1116–1119

[60] Savoldo B, Rooney CM, Di Stasi A, Abken H, Hombach A, Foster AE, Zhang L, Heslop HE, Brenner MK, Dotti G. Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30ζ artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 2007; 110(7): 2620–2630

[61] Ramos CA, Ballard B, Zhang H, Dakhova O, Gee AP, Mei Z, Bilgi M, Wu MF, Liu H, Grilley B, Bollard CM, Chang BH, Rooney CM, Brenner MK, Heslop HE, Dotti G, Savoldo B. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest 2017; 127(9): 3462–3471

[62] Wang CM, Wu ZQ, Wang Y, Guo YL, Dai HR, Wang XH, Li X, Zhang YJ, Zhang WY, Chen MX, Zhang Y, Feng KC, Liu Y, Li SX, Yang QM, Han WD. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma: an open-label phase I trial. Clin Cancer Res 2017; 23(5): 1156–1166

[63] Barrena S, Almeida J, Yunta M, López A, Fernández-Mosteirín N, Giralt M, Romero M, Perdiguer L, Delgado M, Orfao A, Lazo PA. Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation. Leukemia 2005; 19(8): 1376–1383

[64] Pereira DS, Guevara CI, Jin L, Mbong N, Verlinsky A, Hsu SJ, Aviña H, Karki S, Abad JD, Yang P, Moon SJ, Malik F, Choi MY, An Z, Morrison K, Challita-Eid PM, Doñate F, Joseph IB, Kipps TJ, Dick JE, Stover DR. AGS67E, an anti-CD37 monomethyl auristatin E antibody-drug conjugate as a potential therapeutic for B/T-cell malignancies and AML: a new role for CD37 in AML. Mol Cancer Ther 2015; 14(7): 1650–1660

[65] Scarfò I, Ormhøj M, Frigault MJ, Castano AP, Lorrey S, Bouffard AA, van Scoyk A, Rodig SJ, Shay AJ, Aster JC, Preffer FI, Weinstock DM, Maus MV. Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas. Blood 2018; 132(14): 1495–1506

[66] Köksal H, Dillard P, Josefsson SE, Maggadottir SM, Pollmann S, Fåne A, Blaker YN, Beiske K, Huse K, Kolstad A, Holte H, Kvalheim G, Smeland EB, Myklebust JH, Inderberg EM, Wälchli S. Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma. Blood Adv 2019; 3(8): 1230–1243

[67] Ruella M, Xu J, Barrett DM, Fraietta JA, Reich TJ, Ambrose DE, Klichinsky M, Shestova O, Patel PR, Kulikovskaya I, Nazimuddin F, Bhoj VG, Orlando EJ, Fry TJ, Bitter H, Maude SL, Levine BL, Nobles CL, Bushman FD, Young RM, Scholler J, Gill SI, June CH, Grupp SA, Lacey SF, Melenhorst JJ. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med 2018; 24(10): 1499–1503

[68] Calvo KR, McCoy CS, Stetler-Stevenson M. Flow cytometry immunophenotyping of hematolymphoid neoplasia. Methods Mol Biol 2011; 699: 295–316

[69] Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood 2008; 111(8): 3941–3967

[70] Vera J, Savoldo B, Vigouroux S, Biagi E, Pule M, Rossig C, Wu J, Heslop HE, Rooney CM, Brenner MK, Dotti G. T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 2006; 108(12): 3890–3897

[71] Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang H, Dakhova O, Liu E, Carrum G, Kamble RT, Gee AP, Mei Z, Wu MF, Liu H, Grilley B, Rooney CM, Brenner MK, Heslop HE, Dotti G. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest 2016; 126(7): 2588–2596

[72] Wang J, Hu Y, Yang S, Wei G, Zhao X, Wu W, Zhang Y, Zhang Y, Chen D, Wu Z, Xiao L, Chang AH, Huang H, Zhao K. 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

[73] 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): 731–738

[74] Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, Sanvito F, Ponzoni M, Doglioni C, Cristofori P, Traversari C, Bordignon C, Ciceri F, Ostuni R, Bonini C, Casucci M, Bondanza A. 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

[75] Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J, Barrett DM, Weiss SL, Fitzgerald JC, Berg RA, Aplenc R, Callahan C, Rheingold SR, Zheng Z, Rose-John S, White JC, Nazimuddin F, Wertheim G, Levine BL, June CH, Porter DL, Grupp SA. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov 2016; 6(6): 664–679

[76] Wang J, Hu Y, Huang H. Current development of chimeric antigen receptor T-cell therapy. Stem Cell Investig 2018; 5: 44

[77] Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, Komanduri KV, Lin Y, Jain N, Daver N, Westin J, Gulbis AM, Loghin ME, de Groot JF, Adkins S, Davis SE, Rezvani K, Hwu P, Shpall EJ. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol 2018; 15(1): 47–62

[78] Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188–195

[79] Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, Roshal M, Maslak P, Davila M, Brentjens RJ, Sadelain M. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 2018; 378(5): 449–459

[80] 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

[81] Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25(4): 625–638

[82] Chen F, Teachey DT, Pequignot E, Frey N, Porter D, Maude SL, Grupp SA, June CH, Melenhorst JJ, Lacey SF. 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

[83] Sterner RM, Sakemura R, Cox MJ, Yang N, Khadka RH, Forsman CL, Hansen MJ, Jin F, Ayasoufi K, Hefazi M, Schick KJ, Walters DK, Ahmed O, Chappell D, Sahmoud T, Durrant C, Nevala WK, Patnaik MM, Pease LR, Hedin KE, Kay NE, Johnson AJ, Kenderian SS. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood 2019; 133(7): 697–709

[84] Xiao X, He X, Li Q, Zhang H, Meng J, Jiang Y, Deng Q, Zhao M. Plasma exchange can be an alternative therapeutic modality for severe cytokine release syndrome after chimeric antigen receptor-T cell infusion: a case report. Clin Cancer Res 2019; 25(1): 29–34

[85] Fried S, Avigdor A, Bielorai B, Meir A, Besser MJ, Schachter J, Shimoni A, Nagler A, Toren A, Jacoby E. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant 2019; 54(10): 1643–1650

[86] Jain T, Bar M, Kansagra AJ, Chong EA, Hashmi SK, Neelapu SS, Byrne M, Jacoby E, Lazaryan A, Jacobson CA, Ansell SM, Awan FT, Burns L, Bachanova V, Bollard CM, Carpenter PA, DiPersio JF, Hamadani M, Heslop HE, Hill JA, Komanduri KV, Kovitz CA, Lazarus HM, Serrette JM, Mohty M, Miklos D, Nagler A, Pavletic SZ, Savani BN, Schuster SJ, Kharfan-Dabaja MA, Perales MA, Lin Y. Use of chimeric antigen receptor T cell therapy in clinical practice for relapsed/refractory aggressive B cell non-Hodgkin lymphoma: an expert panel opinion from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant 2019; 25(12): 2305–2321

[87] Topp MS, Gökbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. 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(1): 57–66

[88] Hu Y, Sun J, Wu Z, Yu J, Cui Q, Pu C, Liang B, Luo Y, Shi J, Jin A, Xiao L, Huang H. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol 2016; 9(1): 70

[89] Liu D, Zhao J. Cytokine release syndrome: grading, modeling, and new therapy. J Hematol Oncol 2018; 11(1): 121

[90] No authors listed. JCAR015 in ALL: a root-cause investigation. Cancer Discov 2018; 8(1): 4–5

[91] Abramson JS, McGree B, Noyes S, Plummer S, Wong C, Chen YB, Palmer E, Albertson T, Ferry JA, Arrillaga-Romany IC. Anti-CD19 CAR T cells in CNS diffuse large-B-cell lymphoma. N Engl J Med 2017; 377(8): 783–784

[92] Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. 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(9967): 517–528

[93] Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, Halton E, Wang X, Senechal B, Purdon T, Cross JR, Liu H, Vachha B, Chen X, DeAngelis LM, Li D, Bernal Y, Gonen M, Wendel HG, Sadelain M, Brentjens RJ. 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

[94] Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, Yeung C, Liles WC, Wurfel M, Lopez JA, Chen J, Chung D, Harju-Baker S, Özpolat T, Fink KR, Riddell SR, Maloney DG, Turtle CJ. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 2017; 7(12): 1404–1419

[95] Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Reagan PM, Bot A, Rossi JM, Sherman M, Navale L, Jiang Y, Aycock JS, Elias M, Wiezorek JS, Go WY,Miklos DB. 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

[96] Jin A, Feng J, Wang Z, Jiang L, Hu Y, Zhao K, Huang H. Severe dyspnea caused by rapid enlargement of cervical lymph node in a relapsed/refractory B-cell lymphoma patient following chimeric antigen receptor T-cell therapy. Bone Marrow Transplant 2019; 54(7): 969–972

[97] Hu Y, Wang J, Pu C, Zhao K, Cui Q, Wei G, Wu W, Xiao L, Xiao Y, Wang J, Wu Z, Huang H. Delayed terminal ileal perforation in a relapsed/refractory B-cell lymphoma patient with rapid remission following chimeric antigen receptor T-cell therapy. Cancer Res Treat 2018; 50(4): 1462–1466

[98] Hopfinger G, Jäger U, Worel N. CAR-T cell therapy in diffuse large B cell lymphoma: hype and hope. HemaSphere 2019; 3(2): e185

[99] Bhoj VG, Arhontoulis D, Wertheim G, Capobianchi J, Callahan CA, Ellebrecht CT, Obstfeld AE, Lacey SF, Melenhorst JJ, Nazimuddin F, Hwang WT, Maude SL, Wasik MA, Bagg A, Schuster S, Feldman MD, Porter DL, Grupp SA, June CH, Milone MC. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood 2016; 128(3): 360–370

[100] Kansagra AJ, Frey NV, Bar M, Laetsch TW, Carpenter PA, Savani BN, Heslop HE, Bollard CM, Komanduri KV, Gastineau DA, Chabannon C, Perales MA, Hudecek M, Aljurf M, Andritsos L, Barrett JA, Bachanova V, Bonini C, Ghobadi A, Gill SI, Hill JA, Kenderian S, Kebriaei P, Nagler A, Maloney D, Liu HD, Shah NN, Kharfan-Dabaja MA, Shpall EJ, Mufti GJ, Johnston L, Jacoby E, Bazarbachi A, DiPersio JF, Pavletic SZ, Porter DL, Grupp SA, Sadelain M, Litzow MR, Mohty M, Hashmi SK. Clinical utilization of chimeric antigen receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)—an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT). Bone Marrow Transplant 2019; 54(11): 1868–1880

[101] Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371(16): 1507–1517

[102] Avigdor A, Shouval R, Jacoby E, Davidson T, Shimoni A, Besser M, Nagler A. CAR T cells induce a complete response in refractory Burkitt lymphoma. Bone Marrow Transplant 2018; 53(12): 1583–1585

[103] Wang ML, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, Timmerman JM, Holmes H, Jaglowski S, Flinn IW, McSweeney PA, Miklos DB, Pagel JM, Kersten MJ, Peng W, Zheng L, Rossi JM, Jain RK, Rao AV, Reagan PM. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients (Pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL): results of the phase 2 ZUMA-2 study. Blood 2019; 134(Supplement_1): 754

[104] Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, Nandivada V, Kaur I, Nunez Cortes A, Cao K, Daher M, Hosing C, Cohen EN, Kebriaei P, Mehta R, Neelapu S, Nieto Y, Wang M, Wierda W, Keating M, Champlin R, Shpall EJ, Rezvani K. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med 2020; 382(6): 545–553

[105] Cao J, Cheng H, Shi M, Wang G, Chen W, Qi K, Li H, Qiao J, Zhao J, Wu Q, Zeng L, Jing G, Zheng J, Xu K. Humanized CD19-specific chimeric antigen-receptor T-cells in 2 adults with newly diagnosed B-cell acute lymphoblastic leukemia. Leukemia 2019; 33(11): 2751–2753

[106] Ma G, Shen J, Pinz K, Wada M, Park J, Kim S, Togano T, Tse W. Targeting T cell malignancies using CD4CAR T-cells and implementing a natural safety switch. Stem Cell Rev Rep 2019; 15(3): 443–447

[107] Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, Rouce RH, Bao G, Brenner MK, Mamonkin M. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood 2017; 130(3): 285–296

[108] Png YT, Vinanica N, Kamiya T, Shimasaki N, Coustan-Smith E, Campana D. Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies. Blood Adv 2017; 1(25): 2348–2360

[109] Byrne M, Oluwole OO, Savani B, Majhail NS, Hill BT, Locke FL. Understanding and managing large B cell lymphoma relapses after chimeric antigen receptor T cell therapy. Biol Blood Marrow Transplant 2019; 25(11): e344–e351

[110] Walker AJ, Majzner RG, Zhang L, Wanhainen K, Long AH, Nguyen SM, Lopomo P, Vigny M, Fry TJ, Orentas RJ, Mackall CL. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther 2017; 25(9): 2189–2201

[111] Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, Sakemura R, Goto T, Hanajiri R, Imahashi N, Shimada K, Tomita A, Kiyoi H, Nishida T, Naoe T, Murata M. Target antigen density governs the efficacy of anti-CD20-CD28-CD3z chimeric antigen receptor-modified effector CD8⁺ T cells. J Immunol 2015; 194(3): 911–920

[112] Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, Mi T, Switzer K, Singh H, Huls H, Lee DA, Heimberger AB, Champlin RE, Cooper LJ. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res 2015; 75(17): 3505–3518

[113] Turatti F, Figini M, Balladore E, Alberti P, Casalini P, Marks JD, Canevari S, Mezzanzanica D. Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction. J Immunother 2007; 30(7): 684–693

[114] Ying Z, Huang XF, Xiang X, Liu Y, Kang X, Song Y, Guo X, Liu H, Ding N, Zhang T, Duan P, Lin Y, Zheng W, Wang X, Lin N, Tu M, Xie Y, Zhang C, Liu W, Deng L, Gao S, Ping L, Wang X, Zhou N, Zhang J, Wang Y, Lin S, Mamuti M, Yu X, Fang L, Wang S, Song H, Wang G, Jones L, Zhu J, Chen SY. A safe and potent anti-CD19 CAR T cell therapy. Nat Med 2019; 25(6): 947–953

[115] Wang N, Hu X, Cao W, Li C, Xiao Y, Cao Y, Gu C, Zhang S, Chen L, Cheng J, Wang G, Zhou X, Zheng M, Mao X, Jiang L, Wang D, Wang Q, Lou Y, Cai H, Yan D, Zhang Y, Zhang T, Zhou J, Huang L. Efficacy and safety of CAR19/22 T-cell “Cocktail” therapy in patients with refractory/ relapsed B-cell malignancies. Blood 2020; 135(1): 17– 27

[116] Pan J, Zuo S, Deng B, Xu X, Li C, Zheng Q, Ling Z, Song W, Xu J, Duan J, Wang Z, Yu X, Chang AH, Feng X, Tong C. Sequential CD19-22 CAR T therapy induces sustained remission in children with r/r B-ALL. Blood 2020; 135(5): 387–391

[117] Ruella M, Barrett DM, Kenderian SS, Shestova O, Hofmann TJ, Perazzelli J, Klichinsky M, Aikawa V, Nazimuddin F, Kozlowski M, Scholler J, Lacey SF, Melenhorst JJ, Morrissette JJ, Christian DA, Hunter CA, Kalos M, Porter DL, June CH, Grupp SA, Gill S. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest 2016; 126(10): 3814–3826

[118] Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Schönfeld K, Koch J, Dotti G, Heslop HE, Gottschalk S, Wels WS, Baker ML, Ahmed N. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids 2013; 2: e105

[119] Jia H, Wang Z, Wang Y, Liu Y, Dai H, Tong C, Guo Y, Guo B, Ti D, Han X, Yang Q, Wu Z, Han W. Haploidentical CD19/CD22 bispecific CAR-T cells induced MRD-negative remission in a patient with relapsed and refractory adult B-ALL after haploidentical hematopoietic stem cell transplantation. J Hematol Oncol 2019; 12(1): 57

[120] Zhao H, Hu Y, Nagler A, Chang AH, Huang H. CD19/CD22 dual targeted (chimeric antigen receptor) CAR-T therapy for relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). The 46th Annual Meeting of the EBMT. Abstract #O038. 2020

[121] Shah NN, Zhu F, Schneider D, Taylor C, Krueger W, Worden A, Longo WL, Hamadani M, Fenske T, Johnson B, Dropulic B, Orentas R, Hari P. Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma. J Clin Oncol 2019; 37(15_suppl): 2510

[122] Yan ZX, Li L, Wang W, OuYang BS, Cheng S, Wang L, Wu W, Xu PP, Muftuoglu M, Hao M, Yang S, Zhang MC, Zheng Z, Li J, Zhao WL. Clinical efficacy and tumor microenvironment influence in a dose-escalation study of anti-CD19 chimeric antigen receptor T cells in refractory B-cell non-Hodgkin’s lymphoma. Clin Cancer Res 2019; 25(23): 6995–7003

[123] Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015; 15(8): 486–499

[124] Zolov SN, Rietberg SP, Bonifant CL. Programmed cell death protein 1 activation preferentially inhibits CD28.CAR-T cells. Cytotherapy 2018; 20(10): 1259–1266

[125] Wang H, Kaur G, Sankin AI, Chen F, Guan F, Zang X. Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies. J Hematol Oncol 2019; 12(1): 59

[126] Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, June CH, Schuster SJ. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 2017; 129(8): 1039–1041

[127] Hill BT, Roberts ZJ, Xue A, Rossi JM, Smith MR. Rapid tumor regression from PD-1 inhibition after anti-CD19 chimeric antigen receptor T-cell therapy in refractory diffuse large B-cell lymphoma. Bone Marrow Transplant 2020; 55(6): 1184–1187

[128] Suarez ER, Chang K, Sun J, Sui J, Freeman GJ, Signoretti S, Zhu Q, Marasco WA. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 2016; 7(23): 34341–34355

[129] Zhao W, Jia L, Zhang M, Huang X, Qian P, Tang Q, Zhu J, Feng Z. The killing effect of novel bi-specific Trop2/PD-L1 CAR-T cell targeted gastric cancer. Am J Cancer Res 2019; 9(8): 1846–1856

[130] Garfall AL, Stadtmauer EA, Hwang WT, Lacey SF, Melenhorst JJ, Krevvata M, Carroll MP, Matsui WH, Wang Q, Dhodapkar MV, Dhodapkar K, Das R, Vogl DT, Weiss BM, Cohen AD, Mangan PA, Ayers EC, Nunez-Cruz S, Kulikovskaya I, Davis MM, Lamontagne A, Dengel K, Kerr ND, Young RM, Siegel DL, Levine BL, Milone MC, Maus MV, June CH. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. JCI Insight 2018; 3(8): e120505

[131] Sauter CS, Senechal B, Rivière I, Ni A, Bernal Y, Wang X, Purdon T, Hall M, Singh AN, Szenes VZ, Yoo S, Dogan A, Wang Y, Moskowitz CH, Giralt S, Matasar MJ, Perales MA, Curran KJ, Park J, Sadelain M, Brentjens RJ. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood 2019; 134(7): 626–635

[132] DeSelm C, Palomba ML, Yahalom J, Hamieh M, Eyquem J, Rajasekhar VK, Sadelain M. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol Ther 2018; 26(11): 2542–2552

[133] Sim AJ, Jain MD, Figura NB, Chavez JC, Shah BD, Khimani F, Lazaryan A, Krivenko G, Davila ML, Liu HD, Falchook AD, Dahiya S, Rapoport AP, Kim S, Locke FL, Robinson TJ. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys 2019; 105(5): 1012–1021

[134] Mestermann K, Giavridis T, Weber J, Rydzek J, Frenz S, Nerreter T, Mades A, Sadelain M, Einsele H, Hudecek M. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med 2019; 11(499): eaau5907

[135] Weber EW, Lynn RC, Sotillo E, Lattin J, Xu P, Mackall CL. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv 2019; 3(5): 711–717

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81230014, 81470341, 81520108002, and 81500157), the Key Project of Science and Technology Department of Zhejiang Province (No. 2018C03016-2), and the Key Research and Development Program of Zhejiang Province (No. 2019C03016).

Compliance with ethics guidelines

Houli Zhao, Yiyun Wang, Elaine Tan Su Yin, Kui Zhao, Yongxian Hu, and He Huang declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

Open Access

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

RIGHTS & PERMISSIONS

2020 The Author(s) 2020. This article is published with open access at link.springer.com and journal.hep.com.cn