Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment

Abstract

Chimeric antigen receptor (CAR) is a recombinant immunoreceptor combining an antibody-derived targeting fragment with signaling domains capable of activating cells, which endows T cells with the ability to recognize tumor-associated surface antigens independent of the expression of major histocompatibility complex (MHC) molecules. Recent early-phase clinical trials of CAR-modified T (CAR-T) cells for relapsed or refractory B cell malignancies have demonstrated promising results (that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia (B-ALL)). Given this success, broadening the clinical experience of CAR-T cell therapy beyond hematological malignancies has been actively investigated. Here we discuss the basic design of CAR and review the clinical results from the studies of CAR-T cells in B cell leukemia and lymphoma, and several solid tumors. We additionally discuss the major challenges in the further development and strategies for increasing anti-tumor activity and safety, as well as for successful commercial translation.

Key words： chimeric antigen receptor; CAR-T; engineered T cells; adoptive cell therapy; cancer treatment

References

1 Ahmed N, Brawley V, Diouf O, Anderson P, Hicks J, Wang L, Dotti G, Wels W, Liu H, Gee A (2014) Abstract 3500: Tcells redirected against HER2 for the adoptive immunotherapy for HER2-positive osteosarcoma . Cancer Res 72(8 Supplement):3500

2 Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, Liu E, Dakhova O, Ashoori A, Corder A (2015) Human epidermal growth factor receptor 2 (HER2)—specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma . J Clin Oncol 33(15):1688–1696

3 Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M (1999) Highdose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993 . J Clin Oncol 17(7):2105–2116

4 Barrett DM, Zhao Y, Liu X, Jiang S, Carpenito C, Kalos M, Carroll RG, June CH, Grupp SA (2011) Treatment of advanced leukemia in mice with mRNA engineered T cells . Hum Gene Therapy 22 (12):1575–1586

5 Barrett DM, Grupp SA, June CH (2015) Chimeric antigen receptorand TCR-modified T cells enter main street and wall street . J Immunol (Baltimore, Md : 1950) 195(3):755–761

6 Batlevi CL, Matsuki E, Brentjens RJ, Younes A (2016) Novel immunotherapies in lymphoid malignancies . Nat Rev Clin Oncol 13(1):25–40

7 Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, Chew A, Zhao Y, Levine BL, Albelda SM (2014) Mesothelinspecific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies . Cancer Immunol Res 2(2):112–120

8 Beatty GL, O’Hara MH, Nelson AM, McGarvey M, Torigian DA, Lacey SF, Melenhorst JJ, Levine B, Plesa G, June CH (2015) Safety and antitumor activity of chimeric antigen receptor modified T cells in patients with chemotherapy refractory metastatic pancreatic cancer . ASCO Meet Abstr 33 (15_suppl):3007

9 Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ (2016) Toxicity and management in CAR T-cell therapy . Mol Ther Oncolytics 3:16011

10 Boussiotis VA, Freeman GJ, Gribben JG, Nadler LM (1996) The role of B7-1/B7-2:CD28/CLTA-4 pathways in the prevention of anergy, induction of productive immunity and down-regulation of the immune response . Immunol Rev 153:5–26

11 Brentjens R, Yeh R, Bernal Y, Riviere I, Sadelain M (2010) Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial . Mol Ther 18(4):666–668

12 Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O (2011) Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias . Blood 118(18):4817–4828

13 Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M (2013) CD19-targeted Tcells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia . Sci Transl Med 5(177):177ra138

14 Brocker T, Karjalainen K (1995) Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes . J Exp Med 181(5):1653–1659

15 Brocker T, Peter A, Traunecker A, Karjalainen K (1993) New simplified molecular design for functional T cell receptor . Eur J Immunol 23(7):1435–1439

16 Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang W-C, Naranjo A, Starr R, Wagner J, Wright C (2015) Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ Tcells in patients with recurrent glioblastoma . Clin Cancer Res 21 (18):4062

17 Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J (2016) Regression of glioblastoma after chimeric antigen receptor T-cell therapy . N Engl J Med 375(26):2561–2569

18 Brudno JN, Kochenderfer JN (2016) Toxicities of chimeric antigen receptor T cells: recognition and management . Blood 127 (26):3321–3330

19 Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, Gea-Banacloche JC, Pavletic SZ, Hickstein DD, Lu TL(2016) Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease . J Clin Oncol 34 (10):1112–1121

20 Cao Y, Rodgers DT, Du J, Ahmad I, Hampton EN, Ma JS, Mazagova M, Choi SH, Yun HY, Xiao H (2016) Design of switchable chimeric antigen receptor T cells targeting breast cancer . Angew Chem Int Ed Engl 55(26):7520–7524

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

22 Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, Mi T, Switzer K, Singh H, Huls H (2015) Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity . Cancer Res 75(17):3505–3518

23 Chmielewski M, Hombach AA, Abken H (2014) Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma . Immunol Rev 257(1):83–90

24 Choi BD, Suryadevara CM, Gedeon PC, Herndon JE 2nd, Sanchez-Perez L, Bigner DD, Sampson JH (2014) Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma . J Clin Neurosci 21(1):189–190

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

26 Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA (2013) Multiplex genome engineering using CRISPR/Cas systems . Science 339(6121):819–823

27 Cooper LJ (2015) Moving from tinkering in the garage to assembly line production: the manufacture of genetically modified T cells expressing chimeric antigen receptors (CARs) comes on line . Cancer Gene Ther 22(2):64–66

28 Couzin-Frankel J (2013) Breakthrough of the year 2013 . Cancer immunotherapy. Science 342(6165):1432–1433

29 Curran KJ, Pegram HJ, Brentjens RJ (2012) Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions . J Gene Med 14(6):405–415

30 Dai H, Zhang W, Li X, Han Q, Guo Y, Zhang Y, Wang Y, Wang C, Shi F, Zhang Y (2015) Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia . Oncoimmunology 4(11):e1027469

31 Dai H, Wang Y, Lu X, Han W (2016) Chimeric antigen receptors modified T-cells for cancer therapy . J Natl Cancer Inst 108(7):439

32 Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M (2014) Efficacy and toxicity management of 19-28z CAR Tcell therapy in B cell acute lymphoblastic leukemia . Sci Transl Med 6 (224):224ra225

33 de Coana YP, Choudhury A, Kiessling R (2015) Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system . Trends Mol Med 21(8):482–491

34 DeFrancesco L (2016) Juno’s wild ride . Nat Biotechnol 34(8):793

35 Depoil D, Fleire S, Treanor BL, Weber M, Harwood NE, Marchbank KL, Tybulewicz VL, Batista FD (2008) CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand . Nat Immunol 9(1):63–72

36 Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EE, Liang TW, Wong C, Bessette PH, Kamath K, Moore SJ (2013) Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index . Sci Transl Med 5(207):207ra144

37 Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, Heslop HE, Brenner MK, Dotti G, Savoldo B (2009) T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model . Blood 113(25):6392–6402

38 Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B (2011) Inducible apoptosis as a safety switch for adoptive cell therapy . N Engl J Med 365(18):1673–1683

39 Dotti G, Gottschalk S, Savoldo B, Brenner MK (2014) Design and development of therapies using chimeric antigen receptorexpressing T cells . Immunol Rev 257(1):107–126

40 Elert E (2013) Calling cells to arms . Nature 504(7480):S2–S3

41 Eshhar Z (2008) The T-body approach: redirecting T cells with antibody specificity . Handb Exp Pharmacol 181:329–342

42 Eshhar Z (2014) From the mouse cage to human therapy: a personal perspective of the emergence of T-bodies/chimeric antigen receptor T cells . Hum Gene Ther 25(9):773–778

43 Eshhar Z, Waks T, Gross G, Schindler DG (1993) 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 90(2):720–724

44 Evans AG, Rothberg PG, Burack WR, Huntington SF, Porter DL, Friedberg JW, Liesveld JL (2015) Evolution to plasmablastic lymphoma evades CD19-directed chimeric antigen receptor T cells . Br J Haematol 171(2):205–209

45 Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, Odak A, Gonen M, Sadelain M (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection . Nature 543(7643):113–117

46 Fedorov VD, Themeli M, Sadelain M (2013) PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert offtarget immunotherapy responses . Sci Transl Med 5(215):215ra172

47 Feng K, Guo Y, Dai H, Wang Y, Li X, Jia H, Han W (2016) Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer . Sci China Life Sc i 59(5):468–479

48 Fesnak AD, June CH, Levine BL (2016) Engineered T cells: the promise and challenges of cancer immunotherapy . Nat Rev Cancer 16(9):566–581

49 Finney HM, Lawson AD, Bebbington CR, Weir AN (1998) Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product . J Immunol (Baltimore, Md : 1950) 161(6):2791–2797

50 Finney HM, Akbar AN, Lawson ADG (2003) Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR Chain . J Immunol 172 (1):104–113

51 Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy . J Clin Oncol 13(3):688–696

52 Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, Smithers H, Jensen MC, Riddell SR, Maloney DG (2016) Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-Tcell therapy . Blood 127(20):2406–2410

53 Geyer MB, Brentjens RJ (2016) Review: current clinical applications of chimeric antigen receptor (CAR) modified T cells . Cytotherapy 18(11):1393–1409

54 Geyer MB, Park JH, Riviere I, Wang X, Purdon T, Sadelain M, Brentjens RJ (2016) Updated results: phase I trial of autologous CD19-targeted CAR Tcells in patients with residual CLL following initial purine analog-based therapy . ASCO Meet Abstr 34 (15):7526

55 Ghorashian S, Pule M, Amrolia P (2015) CD19 chimeric antigen receptor T cell therapy for haematological malignancies . Br J Haematol 169(4):463–478

56 Gill S, June CH (2015) Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies . Immunol Rev 263(1):68–89

57 Goverman J, Gomez SM, Segesman KD, Hunkapiller T, Laug WE, Hood L (1990) Chimeric immunoglobulin-T cell receptor proteins form functional receptors: implications for T cell receptor complex formation and activation . Cell 60(6):929–939

58 Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Schonfeld K, Koch J, Dotti G (2013) TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy . Mol Ther Nucl Acid 2:e105

59 Gross G, Eshhar Z (2016) Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting offtumor toxicities for safe CAR T cell therapy . Annu Rev Pharmacol Toxicol 56:59–83

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

61 Gross G, Levy S, Levy R, Waks T, Eshhar Z (1995) Chimaeric T-cell receptors specific to a B-lymphoma idiotype: a model for tumour immunotherapy . Biochem Soc Trans 23(4):1079–1082

62 Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia . N Engl J Med 368(16):1509–1518

63 Grupp SA, Maude SL, Shaw PA, Aplenc R, Barrett DM, Callahan C, Lacey SF, Levine BL, Melenhorst JJ, Motley L (2015) Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019) . Blood 126(23):681

64 Guest RD, Hawkins RE, Kirillova N, Cheadle EJ, Arnold J, O’Neill A, Irlam J, Chester KA, Kemshead JT, Shaw DM (2005) The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens . J Immunother (Hagerstown, Md : 1997) 28(3):203–211

65 Hammarstrom S (1999) The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues . Semin Cancer Biol 9(2):67–81

66 Harris DT, Kranz DM (2016) Adoptive T cell therapies: a comparison of T cell receptors and chimeric antigen receptors . Trends Pharmacol Sci 37(3):220–230

67 Haynes NM, Trapani JA, Teng MW, Jackson JT, Cerruti L, Jane SM, Kershaw MH, Smyth MJ, Darcy PK (2002a) Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors . Blood 100(9):3155–3163

68 Haynes NM, Trapani JA, Teng MW, Jackson JT, Cerruti L, Jane SM, Kershaw MH, Smyth MJ, Darcy PK (2002b) Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody receptors codelivering CD28 costimulation . J Immunol (Baltimore, Md : 1950) 169(10):5780–5786

69 Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, Wakefield A, Fousek K, Bielamowicz K, Chow KK (2016) Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape . J Clin Investig 126(8):3036–3052

70 Holohan DR, Lee JC, Bluestone JA (2015) Shifting the evolving CAR T cell platform into higher gear . Cancer Cell 28(4):401–402

71 Hombach A, Heuser C, Sircar R, Tillmann T, Diehl V, Kruis W, Pohl C, Abken H (1997) T cell targeting of TAG72+ tumor cells by a chimeric receptor with antibody-like specificity for a carbohydrate epitope . Gastroenterology 113(4):1163–1170

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

73 Hombach AA, Gorgens A, Chmielewski M, Murke F, Kimpel J, Giebel B, Abken H (2016) Superior therapeutic index in lymphoma therapy: CD30(+) CD34(+) hematopoietic stem cells resist a chimeric antigen receptor T-cell attack . Mol Ther 24 (8):1423–1434

74 Hudecek M, Lupo-Stanghellini MT, Kosasih PL, Sommermeyer D, Jensen MC, Rader C, Riddell SR (2013) Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor Tcells . Clin Cancer Res 19(12):3153–3164

75 Hudecek M, Sommermeyer D, Kosasih PL, Silva-Benedict A, Liu L, Rader C, Jensen MC, Riddell SR (2015) The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity . Cancer Immunol Res 3 (2):125–135

76 Hwu P, Shafer GE, Treisman J, Schindler DG, Gross G, Cowherd R, Rosenberg SA, Eshhar Z (1993) Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain . J Exp Med 178(1):361–366

77 Hwu P, Yang JC, Cowherd R, Treisman J, Shafer GE, Eshhar Z, Rosenberg SA (1995) In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes . Cancer Res 55(15):3369–3373

78 Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors . Nat Rev Cancer 5(5):341–354

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

80 Irving BA, Weiss A (1991) The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways . Cell 64(5):891–901

81 Jackson HJ, Brentjens RJ (2015) Overcoming antigen escape with CAR T-cell therapy . Cancer Discov 5(12):1238–1240

82 Jackson HJ, Rafiq S, Brentjens RJ (2016) Driving CAR T-cells forward . Nat Rev Clin Oncol 13(6):370–383

83 Janka GE (2012) Familial and acquired hemophagocytic lymphohistiocytosis . Annu Rev Med 63:233–246

84 Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, Forman SJ (2010) Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans . Biology Blood Marrow Transpl 16(9):1245–1256

85 Juillerat A, Marechal A, Filhol JM, Valton J, Duclert A, Poirot L, Duchateau P(2016) Design of chimeric antigen receptors with integrated controllable transient functions . Sci Rep 6:18950

86 Junghans RP (2010) Is it safer CARs that we need, or safer rules of the road ? Mol Ther 18(10):1742–1743

87 Junghans RP (2012) Phase IB trial redesign to test role of IL2 with anti-PSMA designer T cells to yield responses in advanced prostate cancer . ASCO Meet Abst 30(5_suppl):70

88 Kalos M (2016) Chimeric antigen receptor-engineered Tcells in CLL: the next chapter unfolds . J Immunother Cancer 4:5

89 Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia . Sci Transl Med 3(95):95ra73

90 Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB(2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer . N Engl J Med 363(5):411–422

91 Katz SC, Burga RA, McCormack E, Wang LJ, Mooring W, Point GR, Khare PD, Thorn M, Ma Q, Stainken BF (2015) Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases . Clin Cancer Res 21 (14):3149–3159

92 Kershaw MH, Teng MW, Smyth MJ, Darcy PK (2005) Supernatural T cells: genetic modification of T cells for cancer therapy . Nat Rev Immunol 5(12):928–940

93 Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer . Clin Cancer Res 12(20 Pt 1):6106–6115

94 Khalil DN, Smith EL, Brentjens RJ, Wolchok JD (2016) The future of cancer treatment: immunomodulation, CARs and combination immunotherapy . Nat Rev Clin Oncol 13(5):273–290

95 Klebanoff CA, Rosenberg SA, Restifo NP (2016) Prospects for gene-engineered T cell immunotherapy for solid cancers . Nat Med 22(1):26–36

96 Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M (2013) Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells . Nat Biotechnol 31(1):71–75

97 Kochenderfer JN, Rosenberg SA (2011) Chimeric antigen receptormodified Tcells in CLL . N Engl J Med 365(20):1937–1938 author reply 1938

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

99 Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM (2012) B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells . Blood 119 (12):2709–2720

100 Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, Hakim FT, Halverson DC, Fowler DH, Hardy NM (2013) Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation . Blood 122(25):4129–4139

101 Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RMl (2015) 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 33(6):540–549

102 Kochenderfer J, Somerville R, Lu T, Shi V, Yang JC, Sherry R, Klebanoff C, Kammula US, Goff SL, Bot A (2016) Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma . ASCO Meet Abstr 34(15_suppl):LBA3010

103 Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N, Smith DD, Forman SJ, Jensen MC, Cooper LJ (2006) CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells . Cancer Res 66(22):10995–11004

104 Kuppers R, Engert A, Hansmann ML (2012) Hodgkin lymphoma . J. Clin Investig 122(10):3439–3447

105 Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, Gratama JW, Stoter G, Oosterwijk E (2006) Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience . J Clin Oncol 24(13):e20–e22

106 Lamers CH, Willemsen R, van Elzakker P, van Steenbergen-Langeveld S, Broertjes M, Oosterwijk-Wakka J, Oosterwijk E, Sleijfer S, Debets R, Gratama JW (2011) Immune responses to transgene and retroviral vector in patients treated with ex vivoengineered T cells . Blood 117(1):72–82

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

108 Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN (2015a) 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) 385 (9967):517–528

109 Lee DW, Stetler-Stevenson M, Yuan CM, Fry TJ, Shah NN C, Delbrook B, Yates H, Zhang L, Zhang JN, Kochenderfer (2015b) Safety and response of incorporatingCD19 chimeric antigen receptor Tcell therapy in typical salvage regimens for children and young adults with acute lymphoblastic leukemia . Blood 126(23):684

110 Leen AM, Rooney CM, Foster AE (2007) Improving Tcell therapy for cancer . Annu Rev Immunol 25:243–265

111 Letourneur F, Klausner RD (1991) T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins . Proc Natl Acad Sci USA 88(20):8905–8909

112 Li G, Wong AJ (2008) EGF receptor variant III as a target antigen for tumor immunotherapy . Expert Rev Vaccines 7(7):977–985

113 Lim WA, June CH (2017) The principles of engineering immune cells to treat cancer . Cell 168(4):724–740

114 Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, Cogdill AP, Li N, Ramones M, Granda B (2015) Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice . Cancer Res 75 (17):3596–3607

115 Liu H, Xu Y, Xiang J, Long L, Green S, Yang Z, Zimdahl B, Lu J, Cheng N, Horan LH(2017a) Targeting alpha-fetoprotein (AFP)-MHC complex with CAR T-cell therapy for liver cancer . Clin Cancer Res 23(2):478–488

116 Liu X, Zhang Y, Cheng C, Cheng AW, Zhang X, Li N, Xia C, Wei X, Liu X, Wang H (2017b) CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells . Cell Res 27(1):154–157

117 Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, Rossig C, Russell HV, Diouf O, Liu E (2011) Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma . Blood 118(23):6050–6056

118 Ma Q, Safar M, Holmes E, Wang Y, Boynton AL, Junghans RP (2004) Anti-prostate specific membrane antigen designer T cells for prostate cancer therapy . Prostate 61(1):12–25

119 Ma Q, Garber HR, Lu S, He H, Tallis E, Ding X, Sergeeva A, Wood MS, Dotti G, Salvado B (2016a) A novel TCR-like CAR with specificity for PR1/HLA-A2 effectively targets myeloid leukemia in vitro when expressed in human adult peripheral blood and cord blood T cells . Cytotherapy 18(8):985–994

120 Ma JS, Kim JY, Kazane SA, Choi SH, Yun HY, Kim MS, Rodgers DT, Pugh HM, Singer O, Sun SB (2016b) Versatile strategy for controlling the specificity and activity of engineered T cells . Proc Natl Acad Sci USA 113(4):E450–E458

121 Maeder ML, Gersbach CA (2016) Genome-editing technologies for gene and cell therapy . Mol Ther 24(3):430–446

122 Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance . Adv Immunol 74:181–273

123 Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SFl (2014a) Chimeric antigen receptor T cells for sustained remissions in leukemia . N Engl J Med 371(16):1507–1517

124 Maude SL, Barrett D, Teachey DT, Grupp SA (2014b) Managing cytokine release syndrome associated with novel T cell-engaging therapies . Cancer J (Sudbury, Mass) 20(2):119–122

125 Maude SL, Teachey DT, Porter DL, Grupp SA (2015a) CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia . Blood 125(26):4017–4023

126 Maude SL, Barrett DM, Ambrose DE, Rheingold SR, Aplenc R, Teachey DT, Callahan C, Barker CS, Mudambi M, Shaw PA (2015b) Efficacy and safety of humanized chimeric antigen receptor (CAR)-modified T cells targeting CD19 in children with relapsed/refractory ALL . Blood 126(23):683

127 Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, Zhao Y, Kalos M, June CH (2013) T cells expressing chimeric antigen receptors can cause anaphylaxis in humans . Cancer Immunol Res 1(1):26–31

128 McGuinness RP, Ge Y, Patel SD, Kashmiri SV, Lee HS, Hand PH, Schlom J, Finer MH, McArthur JG (1999) Anti-tumor activity of human T cells expressing the CC49-zeta chimeric immune receptor . Hum Gene Ther 10(2):165–173

129 Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2 . Mol Ther 18 (4):843–851

130 Nellan A, Lee DW (2015) Paving the road ahead for CD19 CAR T-cell therapy . Curr Opin Hematol 22(6):516–520

131 Newick K, Moon E, Albelda SM (2016) Chimeric antigen receptor T-cell therapy for solid tumors . Mol Ther Oncolytics 3:16006

132 O’Hara M, Stashwick C, Haas AR, Tanyi JL (2016) Mesothelin as a target for chimeric antigen receptor-modified Tcells as anticancer therapy . Immunotherapy 8(4):449–460

133 O’Rourke DM, Nasrallah M, Morrissette JJ, Melenhorst JJ, Lacey SF, Mansfield K, Martinez-Lage M, Desai AS, Brem S, Maloney E (2016) Pilot study of T cells redirected to EGFRvIII with a chimeric antigen receptor in patients with EGFRvIII+ glioblastoma . ASCO Meet Abstr 34(15_suppl):2067

134 Park JH, Riviere I, Wang X, Bernal YJ, Yoo S, Purdon T, Halton E, Quintanilla H, Curran KJ, Sauter CS (2014) CD19-targeted 19-28z CAR modified autologous T cells induce high rates of complete remission and durable responses in adult patients with relapsed, refractory B-cell ALL . Blood 124(21):382

135 Park JH, Riviere I, Wang X, Bernal Y, Purdon T, Halton E, Wang Y, Curran KJ, Sauter CS, Sadelain M (2015) Implications of minimal residual disease negative complete remission (MRD-CR) and allogeneic stem cell transplant on safety and clinical outcome of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed, refractory B-cell ALL . Blood 126(23):682

136 Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, Davis JL, Morgan RA, Merino MJ, Sherry RM (2011) T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis . Mol Ther 19(3):620–626

137 Pastore S, Lulli D, Girolomoni G (2014) Epidermal growth factor receptor signalling in keratinocyte biology: implications for skin toxicity of tyrosine kinase inhibitors . Arch Toxicol 88(6):1189–1203

138 Pegram HJ, Park JH, Brentjens RJ (2014) CD28z CARs and armored CARs . Cancer J 20(2):127–133

139 Pegram HJ, Smith EL, Rafiq S, Brentjens RJ (2015) CAR therapy for hematological cancers: can success seen in the treatment of B-cell acute lymphoblastic leukemia be applied to other hematological malignancies ? Immunotherapy 7(5):545–561

140 Peinert S, Prince HM, Guru PM, Kershaw MH, Smyth MJ, Trapani JA, Gambell P, Harrison S, Scott AM, Smyth FE (2010) Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen . Gene Ther 17(5):678–686

141 Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia . N Engl J Med 365(8):725–733

142 Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia . Sci Transl Med 7(303):303ra139

143 Porter DL, Frey NV, Melenhorst JJ, Hwang W-T, Lacey SF, Shaw PA, Chew A, Marcucci K, Gill S, Loren AW(2016) Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL . ASCO Meet Abstr 34 (15_suppl):3009

144 Posey AD Jr, Schwab RD, Boesteanu AC, Steentoft C, Mandel U, Engels B, Stone JD, Madsen TD, Schreiber K, Haines KM (2016) Engineered CAR T cells targeting the cancer-associated Tn-Glycoform of the membrane mucin MUC1 control adenocarcinoma . Immunity 44(6):1444–1454

145 Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z (2008) Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma . Nat Med 14(11):1264–1270

146 Qasim W, Amrolia PJ, Samarasinghe S, Ghorashian S, Zhan H, Stafford S, Butler K, Ahsan G, Gilmour K, Adams S (2015) First clinical application of Talen engineered universal CAR19 T cells in B-ALL . Blood 126(23):2046

147 Ramos CA, Ballard B, Liu E, Dakhova O, Mei Z, Liu H, Grilley B, Rooney CM, Gee AP, Chang BH (2015) Chimeric T cells for therapy of CD30+ Hodgkin and non-Hodgkin lymphomas . Blood 126(23):185

148 Ratner M (2016) Off-the-shelf CAR-T therapy induces remission in child with ALL . Nat Biotechnol 34(1):12

149 Raufi A, Ebrahim AS, Al-Katib A (2013) Targeting CD19 in B-cell lymphoma: emerging role of SAR3419 . Cancer Manag Res 5:225–233

150 Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y (2016) Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition . Clin Cancer Res.

151 Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, Chen K, Shin M, Wall DM, Honemann D(2013) Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia . Mol The r 21(11):2122–2129

152 Rodgers DT, Mazagova M, Hampton EN, Cao Y, Ramadoss NS, Hardy IR, Schulman A, Du J, Wang F, Singer O (2016) Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies . Proc Natl Acad Sci USA 113(4):E459–E468

153 Romeo C, Seed B (1991) Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides . Cell 64(5):1037–1046

154 Rossig C, Bollard CM, Nuchtern JG, Merchant DA, Brenner MK (2001) Targeting of G(D2)-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes . Int J Cancer 94(2):228–236

155 Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, Lim WA (2016) Precision tumor recognition by T cells with combinatorial antigen-sensing circuits . Cell 164(4):770–779

156 Ruella M, Barrett DM, Kenderian SS, Shestova O, Hofmann TJ, Perazzelli J, Klichinsky M, Aikawa V, Nazimuddin F, Kozlowski M (2016) Dual CD19 and CD123 targeting prevents antigenloss relapses after CD19-directed immunotherapies . J Clin Investig 126(10):3814–3826

157 Ruella M, Kenderian SS, Shestova O, Klichinsky M, Melenhorst JJ, Wasik MA, Lacey SF, June CH, Gill S (2017) Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms . Leukemia 31(1):246–248

158 Sadelain M (2016) Tales of antigen evasion from CAR therapy . Cancer Immunol Res 4(6):473

159 Sadelain M, Brentjens R, Riviere I (2013) The basic principles of chimeric antigen receptor design . Cancer Discov 3(4):388–398

160 Sauter CS, Riviere I, Bernal Y, Wang X, Purdon T, Yoo S, Moskowitz CH, Giralt S, Matasar MJ, Curran KJ (2015) Phase I trial of 19-28z chimeric antigen receptor modified Tcells (19-28z CAR-T) post-high dose therapy and autologous stem cell transplant (HDT-ASCT) for relapsed and refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL) . ASCO Meet Abstr 33 (15_suppl):8515

161 Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients . J Clin Investig 121(5):1822–1826

162 Scheuermann RH, Racila E (1995) CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy . Leuk Lymphoma 18(5–6):385–397

163 Schuster SJ, Svoboda J, Dwivedy Nasta S, Porter DL, Chong EA, Landsburg DJ, Mato AR, Lacey SF, Melenhorst JJ, Chew A (2015) Sustained remissions following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas . Blood 126(23):183

164 Singh N, Perazzelli J, Grupp SA, Barrett DM (2016) Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies . Sci Transl Med 8(320):320

165 Slovin SF, Wang X, Borquez-Ojeda O, Stefanski J, Olszewska M, Taylor C, Bartido S, Scher HI, Sadelain M, Riviere I (2012) Targeting castration resistant prostate cancer (CRPC) with autologous PSMA-directed CAR+ T cells . ASCO Meet Abstr 30 (15):TPS4700

166 Slovin SF, Wang X, Hullings M, Arauz G, Bartido S, Lewis JS, Schoder H, Zanzonico P, Scher HI, Sadelain M (2013) Chimeric antigen receptor (CAR+) modified T cells targeting prostate-specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC). ASCO Meet Abst 31 (6_suppl):72

167 Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, Riddell SR (2016) Chimeric antigen receptormodified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo . Leukemia 30(2):492–500

168 Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, Sussman R, Lanauze C, Ruella M, Gazzara MR (2015) Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy . Cancer Discov 5(12):1282–1295

169 Srivastava S, Riddell SR (2015) Engineering CAR-T cells: design concepts . Trends Immunol 36(8):494–502

170 Stancovski I, Schindler DG, Waks T, Yarden Y, Sela M, Eshhar Z (1993) Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors . J Immunol (Baltimore, Md : 1950) 151(11):6577–6582

171 Tanyi JL, Haas AR, Beatty GL, Morgan MA, Stashwick CJ, O’Hara MH, Porter DL, Maus MV, Levine BL, Lacey SF (2015) Abstract CT105: Safety and feasibility of chimeric antigen receptor modified T cells directed against mesothelin (CARTmeso) in patients with mesothelin expressing cancers . Cancer Res 75(15 Supplement):CT105

172 Tanyi JL, Haas AR, Beatty GL, Stashwick CJ, O’Hara MH, Morgan MA, Porter DL, Melenhorst JJ, Plesa G, Lacey SF (2016) Anti-mesothelin chimeric antigen receptor T cells in patients with epithelial ovarian cancer . ASCO Meet Abst 34(15_suppl):5511

173 Tasian SK, Gardner RA (2015) CD19-redirected chimeric antigen receptor-modified Tcells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL) . Ther Adv Hematol 6(5):228–241

174 Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J (2016) Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia . Cancer Discov 6(6):664–679

175 Terakura S, Yamamoto TN, Gardner RA, Turtle CJ, Jensen MC, Riddell SR (2012) Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells . Blood 119(1):72–82

176 Thaci B, Brown CE, Binello E, Werbaneth K, Sampath P, Sengupta S (2014) Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy . Neuro Oncol 16(10):1304–1312

177 Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ (2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells . Blood 112(6):2261–2271

178 Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE (2012) CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results . Blood 119(17):3940–3950

179 Torikai H, Cooper LJ (2016) Translational implications for off-theshelf immune cells expressing chimeric antigen receptors . Mol Ther 24(7):1178–1186

180 Turtle CJ, Berger C, Sommermeyer D, Hanafi L-A, Pender B, Robinson EM, Melville K, Budiarto TM, Steevens NN, Chaney C (2015) 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 126(23):184

181 Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM (2016a) CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients . J Clin Investig 126(6):2123–2138

182 Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, Hawkins R, Chaney C, Cherian S, Chen X (2016b) Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptormodified T cells . Sci Transl Med 8(355):355ra116

183 US National Library of Science (2016a) ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02614066.

184 US National Library of Science (2016b) ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02535364.

185 US National Library of Science (2016c) ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02228096.

186 US National Library of Science (2016d) ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02030847

187 US National Library of Science (2016e) ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02028455.

188 van der Stegen SJ, Hamieh M, Sadelain M (2015) The pharmacology of second-generation chimeric antigen receptors . Nat Rev Drug Discov 14(7):499–509

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

190 Wang X, Berger C, Wong CW, Forman SJ, Riddell SR, Jensen MC (2011) Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice . Blood 117(6):1888–1898

191 Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, Bo J, Fan H, Zhang Y, Zhang YJ(2014) Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells . Clin Immunol 155(2):160–175

192 Wang X, Popplewell LL, Wagner JR, Naranjo A, Blanchard MS, Mott MR, Norris AP, Wong CW, Urak RZ, Chang WC (2016) Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL . Blood 127(24):2980–2990

193 Wang CM, Wu ZQ, Wang Y, Guo YL, Dai HR, Wang XH, Li X, Zhang YJ, Zhang WY, Chen MX (2017a) Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory hodgkin lymphoma: an open-label phase I trial . Clin Cancer Res 23(5):1156–1166

194 Wang Z, Wu Z, Liu Y,Han W (2017b) New development in CAR-T cell therapy . J Hematol Oncol 10(1):53

195 Whilding LM, Maher J (2015) ErbB-targeted CAR T-cell immunotherapy of cancer . Immunotherapy 7(3):229–241

196 Wilkie S, van Schalkwyk MC, Hobbs S, Davies DM, van der Stegen SJ, Pereira AC, Burbridge SE, Box C, Eccles SA, Maher J (2012) Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling . J Clin Immunol 32(5):1059–1070

197 Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA (2015) Remote control of therapeutic T cells through a small molecule-gated chimeric receptor . Science 350(6258):aab4077

198 Xu XJ, Tang YM (2014) Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells . Cancer Lett 343(2):172–178

199 Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero-Torres A (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas . N Engl J Med 363 (19):1812–1821

200 Yun CO, Nolan KF, Beecham EJ, Reisfeld RA, Junghans RP (2000) Targeting of T lymphocytes to melanoma cells through chimeric anti-GD3 immunoglobulin T-cell receptors . Neoplasia 2(5):449–459

201 Zah E, Lin MY, Silva-Benedict A, Jensen MC, Chen YY (2016) Tcells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells . Cancer Immunol Res 4(6):498–508

202 Zhang G, Wang L, Cui H, Wang X, Zhang G, Ma J, Han H, He W, Wang W, Zhao Y (2014) Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor . Sci Rep 4:3571

203 Zhang T, Cao L, Xie J, Shi N, Zhang Z, Luo Z, Yue D, Zhang Z, Wang L, Han W(2015) Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis . Oncotarget 6(32):33961–33971

204 Zhang W, Wang Y, Guo Y, Dai H, Yang Q, Zhang Y, Zhang Y, Chen M, Wang C, Feng K (2016a) Treatment of CD20-directed chimeric antigen receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report . Signal Transduct Target Ther 1:16002

205 Zhang Y, Zhang W, Dai H, Wang Y, Shi F, Wang C, Guo Y, Liu Y, Chen M, Feng K (2016b) An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T (CAR-T) cells . Sci China Life Sci 59(4):379–385

206 Zhao Y, Moon E, Carpenito C, Paulos CM, Liu X, Brennan AL, Chew A, Carroll RG, Scholler J, Levine BL (2010) Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor . Cancer Res 70(22):9053–9061

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

208 Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M (2010) 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 18(2):413–420