Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment
Zhenguang Wang, Yelei Guo, Weidong Han
Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment
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.
chimeric antigen receptor / CAR-T / engineered T cells / adoptive cell therapy / cancer treatment
[1] |
Ahmed N, Brawley V, Diouf O, Anderson P, Hicks J, Wang L, Dotti G, Wels W, Liu H, Gee A
|
[2] |
Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, Liu E, Dakhova O, Ashoori A, Corder A
CrossRef
Google scholar
|
[3] |
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[6] |
Batlevi CL, Matsuki E, Brentjens RJ, Younes A (2016) Novel immunotherapies in lymphoid malignancies . Nat Rev Clin Oncol 13(1):25–40
CrossRef
Google scholar
|
[7] |
Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, Chew A, Zhao Y, Levine BL, Albelda SM
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[12] |
Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O
CrossRef
Google scholar
|
[13] |
Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[16] |
Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang W-C, Naranjo A, Starr R, Wagner J, Wright C
CrossRef
Google scholar
|
[17] |
Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J
CrossRef
Google scholar
|
[18] |
Brudno JN, Kochenderfer JN (2016) Toxicities of chimeric antigen receptor T cells: recognition and management . Blood 127 (26):3321–3330
CrossRef
Google scholar
|
[19] |
Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, Gea-Banacloche JC, Pavletic SZ, Hickstein DD, Lu TL
CrossRef
Google scholar
|
[20] |
Cao Y, Rodgers DT, Du J, Ahmad I, Hampton EN, Ma JS, Mazagova M, Choi SH, Yun HY, Xiao H
CrossRef
Google scholar
|
[21] |
Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan DF, Albelda SM
CrossRef
Google scholar
|
[22] |
Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, Mi T, Switzer K, Singh H, Huls H
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[26] |
Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[28] |
Couzin-Frankel J (2013) Breakthrough of the year 2013 . Cancer immunotherapy. Science 342(6165):1432–1433
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[30] |
Dai H, Zhang W, Li X, Han Q, Guo Y, Zhang Y, Wang Y, Wang C, Shi F, Zhang Y
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[32] |
Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[34] |
DeFrancesco L (2016) Juno’s wild ride . Nat Biotechnol 34(8):793
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[36] |
Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EE, Liang TW, Wong C, Bessette PH, Kamath K, Moore SJ
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[38] |
Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[40] |
Elert E (2013) Calling cells to arms . Nature 504(7480):S2–S3
CrossRef
Google scholar
|
[41] |
Eshhar Z (2008) The T-body approach: redirecting T cells with antibody specificity . Handb Exp Pharmacol 181:329–342
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[52] |
Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, Smithers H, Jensen MC, Riddell SR, Maloney DG
CrossRef
Google scholar
|
[53] |
Geyer MB, Brentjens RJ (2016) Review: current clinical applications of chimeric antigen receptor (CAR) modified T cells . Cytotherapy 18(11):1393–1409
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[56] |
Gill S, June CH (2015) Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies . Immunol Rev 263(1):68–89
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[58] |
Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Schonfeld K, Koch J, Dotti G
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[62] |
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF
CrossRef
Google scholar
|
[63] |
Grupp SA, Maude SL, Shaw PA, Aplenc R, Barrett DM, Callahan C, Lacey SF, Levine BL, Melenhorst JJ, Motley L
|
[64] |
Guest RD, Hawkins RE, Kirillova N, Cheadle EJ, Arnold J, O’Neill A, Irlam J, Chester KA, Kemshead JT, Shaw DM
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[70] |
Holohan DR, Lee JC, Bluestone JA (2015) Shifting the evolving CAR T cell platform into higher gear . Cancer Cell 28(4):401–402
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[81] |
Jackson HJ, Brentjens RJ (2015) Overcoming antigen escape with CAR T-cell therapy . Cancer Discov 5(12):1238–1240
CrossRef
Google scholar
|
[82] |
Jackson HJ, Rafiq S, Brentjens RJ (2016) Driving CAR T-cells forward . Nat Rev Clin Oncol 13(6):370–383
CrossRef
Google scholar
|
[83] |
Janka GE (2012) Familial and acquired hemophagocytic lymphohistiocytosis . Annu Rev Med 63:233–246
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[86] |
Junghans RP (2010) Is it safer CARs that we need, or safer rules of the road ? Mol Ther 18(10):1742–1743
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[88] |
Kalos M (2016) Chimeric antigen receptor-engineered Tcells in CLL: the next chapter unfolds . J Immunother Cancer 4:5
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[90] |
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB
CrossRef
Google scholar
|
[91] |
Katz SC, Burga RA, McCormack E, Wang LJ, Mooring W, Point GR, Khare PD, Thorn M, Ma Q, Stainken BF
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[93] |
Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[95] |
Klebanoff CA, Rosenberg SA, Restifo NP (2016) Prospects for gene-engineered T cell immunotherapy for solid cancers . Nat Med 22(1):26–36
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[99] |
Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM
CrossRef
Google scholar
|
[100] |
Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, Hakim FT, Halverson DC, Fowler DH, Hardy NM
CrossRef
Google scholar
|
[101] |
Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM
CrossRef
Google scholar
|
[102] |
Kochenderfer J, Somerville R, Lu T, Shi V, Yang JC, Sherry R, Klebanoff C, Kammula US, Goff SL, Bot A
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[104] |
Kuppers R, Engert A, Hansmann ML (2012) Hodgkin lymphoma . J. Clin Investig 122(10):3439–3447
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[108] |
Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN
CrossRef
Google scholar
|
[109] |
Lee DW, Stetler-Stevenson M, Yuan CM, Fry TJ, Shah NN C, Delbrook B, Yates H, Zhang L, Zhang JN, Kochenderfer
|
[110] |
Leen AM, Rooney CM, Foster AE (2007) Improving Tcell therapy for cancer . Annu Rev Immunol 25:243–265
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[112] |
Li G, Wong AJ (2008) EGF receptor variant III as a target antigen for tumor immunotherapy . Expert Rev Vaccines 7(7):977–985
CrossRef
Google scholar
|
[113] |
Lim WA, June CH (2017) The principles of engineering immune cells to treat cancer . Cell 168(4):724–740
CrossRef
Google scholar
|
[114] |
Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, Cogdill AP, Li N, Ramones M, Granda B
CrossRef
Google scholar
|
[115] |
Liu H, Xu Y, Xiang J, Long L, Green S, Yang Z, Zimdahl B, Lu J, Cheng N, Horan LH
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[117] |
Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, Rossig C, Russell HV, Diouf O, Liu E
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[119] |
Ma Q, Garber HR, Lu S, He H, Tallis E, Ding X, Sergeeva A, Wood MS, Dotti G, Salvado B
CrossRef
Google scholar
|
[120] |
Ma JS, Kim JY, Kazane SA, Choi SH, Yun HY, Kim MS, Rodgers DT, Pugh HM, Singer O, Sun SB
CrossRef
Google scholar
|
[121] |
Maeder ML, Gersbach CA (2016) Genome-editing technologies for gene and cell therapy . Mol Ther 24(3):430–446
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[123] |
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[126] |
Maude SL, Barrett DM, Ambrose DE, Rheingold SR, Aplenc R, Teachey DT, Callahan C, Barker CS, Mudambi M, Shaw PA
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[130] |
Nellan A, Lee DW (2015) Paving the road ahead for CD19 CAR T-cell therapy . Curr Opin Hematol 22(6):516–520
CrossRef
Google scholar
|
[131] |
Newick K, Moon E, Albelda SM (2016) Chimeric antigen receptor T-cell therapy for solid tumors . Mol Ther Oncolytics 3:16006
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[133] |
O’Rourke DM, Nasrallah M, Morrissette JJ, Melenhorst JJ, Lacey SF, Mansfield K, Martinez-Lage M, Desai AS, Brem S, Maloney E
|
[134] |
Park JH, Riviere I, Wang X, Bernal YJ, Yoo S, Purdon T, Halton E, Quintanilla H, Curran KJ, Sauter CS
|
[135] |
Park JH, Riviere I, Wang X, Bernal Y, Purdon T, Halton E, Wang Y, Curran KJ, Sauter CS, Sadelain M
|
[136] |
Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, Davis JL, Morgan RA, Merino MJ, Sherry RM
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[138] |
Pegram HJ, Park JH, Brentjens RJ (2014) CD28z CARs and armored CARs . Cancer J 20(2):127–133
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[140] |
Peinert S, Prince HM, Guru PM, Kershaw MH, Smyth MJ, Trapani JA, Gambell P, Harrison S, Scott AM, Smyth FE
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[142] |
Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V
CrossRef
Google scholar
|
[143] |
Porter DL, Frey NV, Melenhorst JJ, Hwang W-T, Lacey SF, Shaw PA, Chew A, Marcucci K, Gill S, Loren AW
|
[144] |
Posey AD Jr, Schwab RD, Boesteanu AC, Steentoft C, Mandel U, Engels B, Stone JD, Madsen TD, Schreiber K, Haines KM
CrossRef
Google scholar
|
[145] |
Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z
CrossRef
Google scholar
|
[146] |
Qasim W, Amrolia PJ, Samarasinghe S, Ghorashian S, Zhan H, Stafford S, Butler K, Ahsan G, Gilmour K, Adams S
|
[147] |
Ramos CA, Ballard B, Liu E, Dakhova O, Mei Z, Liu H, Grilley B, Rooney CM, Gee AP, Chang BH
|
[148] |
Ratner M (2016) Off-the-shelf CAR-T therapy induces remission in child with ALL . Nat Biotechnol 34(1):12
CrossRef
Google scholar
|
[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.
CrossRef
Google scholar
|
[151] |
Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, Chen K, Shin M, Wall DM, Honemann D
CrossRef
Google scholar
|
[152] |
Rodgers DT, Mazagova M, Hampton EN, Cao Y, Ramadoss NS, Hardy IR, Schulman A, Du J, Wang F, Singer O
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[156] |
Ruella M, Barrett DM, Kenderian SS, Shestova O, Hofmann TJ, Perazzelli J, Klichinsky M, Aikawa V, Nazimuddin F, Kozlowski M
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[159] |
Sadelain M, Brentjens R, Riviere I (2013) The basic principles of chimeric antigen receptor design . Cancer Discov 3(4):388–398
CrossRef
Google scholar
|
[160] |
Sauter CS, Riviere I, Bernal Y, Wang X, Purdon T, Yoo S, Moskowitz CH, Giralt S, Matasar MJ, Curran KJ
|
[161] |
Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z
CrossRef
Google scholar
|
[162] |
Scheuermann RH, Racila E (1995) CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy . Leuk Lymphoma 18(5–6):385–397
CrossRef
Google scholar
|
[163] |
Schuster SJ, Svoboda J, Dwivedy Nasta S, Porter DL, Chong EA, Landsburg DJ, Mato AR, Lacey SF, Melenhorst JJ, Chew A
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[169] |
Srivastava S, Riddell SR (2015) Engineering CAR-T cells: design concepts . Trends Immunol 36(8):494–502
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[172] |
Tanyi JL, Haas AR, Beatty GL, Stashwick CJ, O’Hara MH, Morgan MA, Porter DL, Melenhorst JJ, Plesa G, Lacey SF
|
[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
CrossRef
Google scholar
|
[174] |
Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[177] |
Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ
CrossRef
Google scholar
|
[178] |
Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE
CrossRef
Google scholar
|
[179] |
Torikai H, Cooper LJ (2016) Translational implications for off-theshelf immune cells expressing chimeric antigen receptors . Mol Ther 24(7):1178–1186
CrossRef
Google scholar
|
[180] |
Turtle CJ, Berger C, Sommermeyer D, Hanafi L-A, Pender B, Robinson EM, Melville K, Budiarto TM, Steevens NN, Chaney C
|
[181] |
Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM
CrossRef
Google scholar
|
[182] |
Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, Hawkins R, Chaney C, Cherian S, Chen X
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[189] |
Wang J, Jensen M, Lin Y, Sui X, Chen E, Lindgren CG, Till B, Raubitschek A, Forman SJ, Qian X
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[191] |
Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, Bo J, Fan H, Zhang Y, Zhang YJ
CrossRef
Google scholar
|
[192] |
Wang X, Popplewell LL, Wagner JR, Naranjo A, Blanchard MS, Mott MR, Norris AP, Wong CW, Urak RZ, Chang WC
CrossRef
Google scholar
|
[193] |
Wang CM, Wu ZQ, Wang Y, Guo YL, Dai HR, Wang XH, Li X, Zhang YJ, Zhang WY, Chen MX
CrossRef
Google scholar
|
[194] |
Wang Z, Wu Z, Liu Y,Han W (2017b) New development in CAR-T cell therapy . J Hematol Oncol 10(1):53
CrossRef
Google scholar
|
[195] |
Whilding LM, Maher J (2015) ErbB-targeted CAR T-cell immunotherapy of cancer . Immunotherapy 7(3):229–241
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[202] |
Zhang G, Wang L, Cui H, Wang X, Zhang G, Ma J, Han H, He W, Wang W, Zhao Y
CrossRef
Google scholar
|
[203] |
Zhang T, Cao L, Xie J, Shi N, Zhang Z, Luo Z, Yue D, Zhang Z, Wang L, Han W
CrossRef
Google scholar
|
[204] |
Zhang W, Wang Y, Guo Y, Dai H, Yang Q, Zhang Y, Zhang Y, Chen M, Wang C, Feng K
CrossRef
Google scholar
|
[205] |
Zhang Y, Zhang W, Dai H, Wang Y, Shi F, Wang C, Guo Y, Liu Y, Chen M, Feng K
CrossRef
Google scholar
|
[206] |
Zhao Y, Moon E, Carpenito C, Paulos CM, Liu X, Brennan AL, Chew A, Carroll RG, Scholler J, Levine BL
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
[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
CrossRef
Google scholar
|
/
〈 | 〉 |