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Targeted immunotherapy of cancer with CAR T cells: achievements and challenges

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Abstract

The adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a relatively new but promising approach in the field of cancer immunotherapy. This therapeutic strategy is based on the genetic reprogramming of T cells with an artificial immune receptor that redirects them against targets on malignant cells and enables their destruction by exerting T cell effector functions. There has been an explosion of interest in the use of CAR T cells as an immunotherapy for cancer. In the pre-clinical setting, there has been a considerable focus upon optimizing the structural and signaling potency of the CAR while advances in bio-processing technology now mean that the clinical testing of these gene-modified T cells has become a reality. This review will summarize the concept of CAR-based immunotherapy and recent clinical trial activity and will further discuss some of the likely future challenges facing CAR-modified T cell therapies.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Garrido F, Cabrera T, Concha A, Glew S, Ruiz-Cabello F, Stern PL (1993) Natural history of HLA expression during tumour development. Immunol Today 14(10):491–499

    Article  PubMed  CAS  Google Scholar 

  3. Mezzanzanica D, Canevari S, Mazzoni A, Figini M, Colnaghi MI, Waks T, Schindler DG, Eshhar Z (1998) Transfer of chimeric receptor gene made of variable regions of tumor-specific antibody confers anticarbohydrate specificity on T cells. Cancer Gene Ther 5(6):401–407

    PubMed  CAS  Google Scholar 

  4. 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

    Article  PubMed  CAS  Google Scholar 

  5. Murphy A, Westwood JA, Teng MW, Moeller M, Darcy PK, Kershaw MH (2005) Gene modification strategies to induce tumor immunity. Immunity 22(4):403–414

    Article  PubMed  CAS  Google Scholar 

  6. Brenner MK, Heslop HE (2010) Adoptive T cell therapy of cancer. Curr Opin Immunol 22(2):251–257. doi:10.1016/j.coi.2010.01.020

    Article  PubMed  CAS  Google Scholar 

  7. Bridgeman JS, Hawkins RE, Hombach AA, Abken H, Gilham DE (2010) Building better chimeric antigen receptors for adoptive T cell therapy. Curr Gene Ther 10(2):77–90

    Article  PubMed  CAS  Google Scholar 

  8. Kalos M (2012) Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. Cancer Immunol Immunother 61(1):127–135. doi:10.1007/s00262-011-1173-5

    Article  PubMed  CAS  Google Scholar 

  9. Chmielewski M, Abken H (2012) CAR T cells transform to trucks: chimeric antigen receptor-redirected T cells engineered to deliver inducible IL-12 modulate the tumour stroma to combat cancer. Cancer Immunol Immunother. doi:10.1007/s00262-012-1202-z

    PubMed  Google Scholar 

  10. Bird RE, Hardman KD, Jacobson JW, Johnson S, Kaufman BM, Lee SM, Lee T, Pope SH, Riordan GS, Whitlow M (1988) Single-chain antigen-binding proteins. Science 242(4877):423–426

    Article  PubMed  CAS  Google Scholar 

  11. Altenschmidt U, Kahl R, Moritz D, Schnierle BS, Gerstmayer B, Wels W, Groner B (1996) Cytolysis of tumor cells expressing the Neu/erbB-2, erbB-3, and erbB-4 receptors by genetically targeted naive T lymphocytes. Clin Cancer Res 2(6):1001–1008

    PubMed  CAS  Google Scholar 

  12. Kahlon KS, Brown C, Cooper LJ, Raubitschek A, Forman SJ, Jensen MC (2004) Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res 64(24):9160–9166. doi:10.1158/0008-5472.CAN-04-0454

    Article  PubMed  CAS  Google Scholar 

  13. Zhang T, Lemoi BA, Sentman CL (2005) Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. Blood 106(5):1544–1551. doi:10.1182/blood-2004-11-4365

    Article  PubMed  CAS  Google Scholar 

  14. Zhang T, Barber A, Sentman CL (2007) Chimeric NKG2D modified T cells inhibit systemic T-cell lymphoma growth in a manner involving multiple cytokines and cytotoxic pathways. Cancer Res 67(22):11029–11036. doi:10.1158/0008-5472.CAN-07-2251

    Article  PubMed  CAS  Google Scholar 

  15. Gong MC, Latouche JB, Krause A, Heston WD, Bander NH, Sadelain M (1999) Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. Neoplasia 1(2):123–127

    Article  PubMed  CAS  Google Scholar 

  16. 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 161(6):2791–2797

    PubMed  CAS  Google Scholar 

  17. Darcy PK, Kershaw MH, Trapani JA, Smyth MJ (1998) Expression in cytotoxic T lymphocytes of a single-chain anti-carcinoembryonic antigen antibody. Redirected Fas ligand-mediated lysis of colon carcinoma. Eur J Immunol 28(5):1663–1672. doi:10.1002/(SICI)1521-4141(199805)28:05<1663::AID-IMMU1663>3.0.CO;2-L

    Google Scholar 

  18. Patel SD, Moskalenko M, Smith D, Maske B, Finer MH, McArthur JG (1999) Impact of chimeric immune receptor extracellular protein domains on T cell function. Gene Ther 6(3):412–419. doi:10.1038/sj.gt.3300831

    Article  PubMed  CAS  Google Scholar 

  19. Hombach A, Sircar R, Heuser C, Tillmann T, Diehl V, Kruis W, Pohl C, Abken H (1998) Chimeric anti-TAG72 receptors with immunoglobulin constant Fc domains and gamma or zeta signalling chains. Int J Mol Med 2(1):99–103

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. Hombach AA, Schildgen V, Heuser C, Finnern R, Gilham DE, Abken H (2007) T cell activation by antibody-like immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected T cells. J Immunol 178(7):4650–4657

    PubMed  CAS  Google Scholar 

  22. 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

    Article  PubMed  CAS  Google Scholar 

  23. Eshhar Z, Waks T, Bendavid A, Schindler DG (2001) Functional expression of chimeric receptor genes in human T cells. J Immunol Methods 248(1–2):67–76

    Article  PubMed  CAS  Google Scholar 

  24. Bridgeman JS, Hawkins RE, Bagley S, Blaylock M, Holland M, Gilham DE (2010) The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol 184(12):6938–6949. doi:10.4049/jimmunol.0901766

    Article  PubMed  CAS  Google Scholar 

  25. Ren-Heidenreich L, Mordini R, Hayman GT, Siebenlist R, LeFever A (2002) Comparison of the TCR zeta-chain with the FcR gamma-chain in chimeric TCR constructs for T cell activation and apoptosis. Cancer Immunol Immunother 51(8):417–423. doi:10.1007/s00262-002-0301-7

    Article  PubMed  CAS  Google Scholar 

  26. Haynes NM, Snook MB, Trapani JA, Cerruti L, Jane SM, Smyth MJ, Darcy PK (2001) Redirecting mouse CTL against colon carcinoma: superior signaling efficacy of single-chain variable domain chimeras containing TCR-zeta vs Fc epsilon RI-gamma. J Immunol 166(1):182–187

    PubMed  CAS  Google Scholar 

  27. Brentjens RJ, Latouche JB, Santos E, Marti F, Gong MC, Lyddane C, King PD, Larson S, Weiss M, Riviere I, Sadelain M (2003) Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9(3):279–286. doi:10.1038/nm827

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. Alvarez-Vallina L, Hawkins RE (1996) Antigen-specific targeting of CD28-mediated T cell co-stimulation using chimeric single-chain antibody variable fragment-CD28 receptors. Eur J Immunol 26(10):2304–2309. doi:10.1002/eji.1830261006

    Article  PubMed  CAS  Google Scholar 

  30. Beecham EJ, Ortiz-Pujols S, Junghans RP (2000) Dynamics of tumor cell killing by human T lymphocytes armed with an anti-carcinoembryonic antigen chimeric immunoglobulin T-cell receptor. J Immunother 23(3):332–343

    Article  PubMed  CAS  Google Scholar 

  31. Brentjens RJ, Santos E, Nikhamin Y, Yeh R, Matsushita M, La Perle K, Quintas-Cardama A, Larson SM, Sadelain M (2007) Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 13(18 Pt 1):5426–5435. doi:10.1158/1078-0432.CCR-07-0674

    Article  PubMed  CAS  Google Scholar 

  32. Friedmann-Morvinski D, Bendavid A, Waks T, Schindler D, Eshhar Z (2005) Redirected primary T cells harboring a chimeric receptor require costimulation for their antigen-specific activation. Blood 105(8):3087–3093. doi:10.1182/blood-2004-09-3737

    Article  PubMed  CAS  Google Scholar 

  33. Loskog A, Giandomenico V, Rossig C, Pule M, Dotti G, Brenner MK (2006) Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells. Leukemia 20(10):1819–1828. doi:10.1038/sj.leu.2404366

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  35. Pinthus JH, Waks T, Kaufman-Francis K, Schindler DG, Harmelin A, Kanety H, Ramon J, Eshhar Z (2003) Immuno-gene therapy of established prostate tumors using chimeric receptor-redirected human lymphocytes. Cancer Res 63(10):2470–2476

    PubMed  CAS  Google Scholar 

  36. Teng MW, Kershaw MH, Moeller M, Smyth MJ, Darcy PK (2004) Immunotherapy of cancer using systemically delivered gene-modified human T lymphocytes. Hum Gene Ther 15(7):699–708

    Article  PubMed  CAS  Google Scholar 

  37. Hombach A, Sent D, Schneider C, Heuser C, Koch D, Pohl C, Seliger B, Abken H (2001) T-cell activation by recombinant receptors: CD28 costimulation is required for interleukin 2 secretion and receptor-mediated T-cell proliferation but does not affect receptor-mediated target cell lysis. Cancer Res 61(5):1976–1982

    PubMed  CAS  Google Scholar 

  38. Pule MA, Straathof KC, Dotti G, Heslop HE, Rooney CM, Brenner MK (2005) A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther 12(5):933–941. doi:10.1016/j.ymthe.2005.04.016

    Article  PubMed  CAS  Google Scholar 

  39. Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss B, Danet-Desnoyers G, Campana D, Riley JL, Grupp SA, June CH (2009) Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17(8):1453–1464. doi:10.1038/mt.2009.83

    Article  PubMed  CAS  Google Scholar 

  40. Finney HM, Akbar AN, Lawson AD (2004) 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 zeta chain. J Immunol 172(1):104–113

    PubMed  CAS  Google Scholar 

  41. Song DG, Ye Q, Carpenito C, Poussin M, Wang LP, Ji C, Figini M, June CH, Coukos G, Powell DJ Jr (2011) In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res 71(13):4617–4627. doi:10.1158/0008-5472.CAN-11-0422

    Article  PubMed  CAS  Google Scholar 

  42. 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 (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. doi:10.1073/pnas.0813101106

    Article  PubMed  CAS  Google Scholar 

  43. Cheadle EJ, Rothwell DG, Bridgeman JS, Sheard VE, Hawkins RE, Gilham DE (2011) Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells. Gene Ther. doi:10.1038/gt.2011.192

  44. Fitzer-Attas CJ, Schindler DG, Waks T, Eshhar Z (1998) Harnessing Syk family tyrosine kinases as signaling domains for chimeric single chain of the variable domain receptors: optimal design for T cell activation. J Immunol 160(1):145–154

    PubMed  CAS  Google Scholar 

  45. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, Hwu P (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

    Article  PubMed  CAS  Google Scholar 

  46. 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

    Article  PubMed  Google Scholar 

  47. Lamers CH, Langeveld SC, Groot-van Ruijven CM, Debets R, Sleijfer S, Gratama JW (2007) Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo. Cancer Immunol Immunother 56(12):1875–1883. doi:10.1007/s00262-007-0330-3

    Article  PubMed  Google Scholar 

  48. Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC (2007) Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 15(4):825–833

    PubMed  CAS  Google Scholar 

  49. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z, Yvon E, Weiss HL, Liu H, Rooney CM, Heslop HE, Brenner MK (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. doi:10.1038/nm.1882

    Article  PubMed  CAS  Google Scholar 

  50. Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ, Gopal AK, Pagel JM, Lindgren CG, Greenberg PD, Riddell SR, Press OW (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. doi:10.1182/blood-2007-12-128843

    Article  PubMed  CAS  Google Scholar 

  51. Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, Rossig C, Russell HV, Diouf O, Liu E, Liu H, Wu MF, Gee AP, Mei Z, Rooney CM, Heslop HE, Brenner MK (2011) Anti-tumor activity and long-term fate of chimeric antigen receptor positive T-cells in patients with neuroblastoma. Blood. doi:10.1182/blood-2011-05-354449

  52. 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. doi:10.1056/NEJMoa1103849

    Article  PubMed  CAS  Google Scholar 

  53. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA (2011) 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. doi:10.1182/blood-2011-10-384388

  54. 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

    Article  PubMed  CAS  Google Scholar 

  55. Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, Olszewska M, Bernal Y, Pegram H, Przybylowski M, Hollyman D, Usachenko Y, Pirraglia D, Hosey J, Santos E, Halton E, Maslak P, Scheinberg D, Jurcic J, Heaney M, Heller G, Frattini M, Sadelain M (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. doi:10.1182/blood-2011-04-348540

    Article  PubMed  CAS  Google Scholar 

  56. 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 (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. doi:10.1182/blood-2010-04-281931

    Article  PubMed  CAS  Google Scholar 

  57. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z, Liu H, Grilley B, Rooney CM, Heslop HE, Brenner MK, Dotti G (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 121(5):1822–1826. doi:10.1172/JCI46110

    Article  PubMed  CAS  Google Scholar 

  58. 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. doi:10.1038/mt.2010.31

    Article  PubMed  CAS  Google Scholar 

  59. 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. doi:10.1038/mt.2010.24

    Article  PubMed  CAS  Google Scholar 

  60. Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112(12):4371–4383. doi:10.1182/blood-2008-03-077974

    Article  PubMed  CAS  Google Scholar 

  61. Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M, Turchetto L, Colombi S, Bernardi M, Peccatori J, Pescarollo A, Servida P, Magnani Z, Perna SK, Valtolina V, Crippa F, Callegaro L, Spoldi E, Crocchiolo R, Fleischhauer K, Ponzoni M, Vago L, Rossini S, Santoro A, Todisco E, Apperley J, Olavarria E, Slavin S, Weissinger EM, Ganser A, Stadler M, Yannaki E, Fassas A, Anagnostopoulos A, Bregni M, Stampino CG, Bruzzi P, Bordignon C (2009) Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol 10(5):489–500. doi:10.1016/S1470-2045(09)70074-9

    Article  PubMed  Google Scholar 

  62. 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. Biol Blood Marrow Transplant 16(9):1245–1256. doi:10.1016/j.bbmt.2010.03.014

    Article  PubMed  CAS  Google Scholar 

  63. Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J, Heslop HE, Rooney CM, Brenner MK, Dotti G (2010) Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24(6):1160–1170. doi:10.1038/leu.2010.75

    Article  PubMed  CAS  Google Scholar 

  64. Sadelain M, Riviere I, Brentjens R (2003) Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer 3(1):35–45

    Article  PubMed  CAS  Google Scholar 

  65. Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 348(3):255–256

    Article  PubMed  Google Scholar 

  66. Bonini C, Grez M, Traversari C, Ciceri F, Marktel S, Ferrari G, Dinauer M, Sadat M, Aiuti A, Deola S, Radrizzani M, Hagenbeek A, Apperley J, Ebeling S, Martens A, Kolb HJ, Weber M, Lotti F, Grande A, Weissinger E, Bueren JA, Lamana M, Falkenburg JH, Heemskerk MH, Austin T, Kornblau S, Marini F, Benati C, Magnani Z, Cazzaniga S, Toma S, Gallo-Stampino C, Introna M, Slavin S, Greenberg PD, Bregni M, Mavilio F, Bordignon C (2003) Safety of retroviral gene marking with a truncated NGF receptor. Nat Med 9(4):367–369. doi:10.1038/nm0403-367

    Article  PubMed  CAS  Google Scholar 

  67. Brenner MK, Heslop HE (2003) Is retroviral gene marking too dangerous to use? Cytotherapy 5(3):190–193. doi:10.1080/14653240310001307

    Article  PubMed  CAS  Google Scholar 

  68. Banasik MB, McCray PB Jr (2010) Integrase-defective lentiviral vectors: progress and applications. Gene Ther 17(2):150–157. doi:10.1038/gt.2009.135

    Article  PubMed  CAS  Google Scholar 

  69. Dotti G, Savoldo B, Brenner M (2009) Fifteen years of gene therapy based on chimeric antigen receptors: “are we nearly there yet?”. Hum Gene Ther 20(11):1229–1239. doi:10.1089/hum.2009.142

    Article  PubMed  CAS  Google Scholar 

  70. 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 Ther 22(12):1575–1586. doi:10.1089/hum.2011.070

    Article  PubMed  CAS  Google Scholar 

  71. Rabinovich PM, Komarovskaya ME, Wrzesinski SH, Alderman JL, Budak-Alpdogan T, Karpikov A, Guo H, Flavell RA, Cheung NK, Weissman SM, Bahceci E (2009) Chimeric receptor mRNA transfection as a tool to generate antineoplastic lymphocytes. Hum Gene Ther 20(1):51–61. doi:10.1089/hum.2008.068

    Article  PubMed  CAS  Google Scholar 

  72. Rabinovich PM, Komarovskaya ME, Ye ZJ, Imai C, Campana D, Bahceci E, Weissman SM (2006) Synthetic messenger RNA as a tool for gene therapy. Hum Gene Ther 17(10):1027–1035

    Article  PubMed  CAS  Google Scholar 

  73. Zhao Y, Moon E, Carpenito C, Paulos CM, Liu X, Brennan AL, Chew A, Carroll RG, Scholler J, Levine BL, Albelda SM, June CH (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. doi:10.1158/0008-5472.CAN-10-2880

    Article  PubMed  CAS  Google Scholar 

  74. 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 vivo-engineered T cells. Blood 117(1):72–82. doi:10.1182/blood-2010-07-294520

    Article  PubMed  CAS  Google Scholar 

  75. Westwood JA, Smyth MJ, Teng MW, Moeller M, Trapani JA, Scott AM, Smyth FE, Cartwright GA, Power BE, Honemann D, Prince HM, Darcy PK, Kershaw MH (2005) Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y-expressing tumors in mice. Proc Natl Acad Sci USA 102(52):19051–19056. doi:10.1073/pnas.0504312102

    Article  PubMed  CAS  Google Scholar 

  76. Shibaguchi H, Luo NX, Kuroki M, Zhao J, Huang J, Hachimine K, Kinugasa T, Kuroki M (2006) A fully human chimeric immune receptor for retargeting T-cells to CEA-expressing tumor cells. Anticancer Res 26(6A):4067–4072

    PubMed  CAS  Google Scholar 

  77. Welniak LA, Blazar BR, Murphy WJ (2007) Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 25:139–170. doi:10.1146/annurev.immunol.25.022106.141606

    Article  PubMed  CAS  Google Scholar 

  78. Marcus A, Waks T, Eshhar Z (2011) Redirected tumor-specific allogeneic T cells for universal treatment of cancer. Blood 118(4):975–983. doi:10.1182/blood-2011-02-334284

    Article  PubMed  CAS  Google Scholar 

  79. Hinrichs CS, Borman ZA, Cassard L, Gattinoni L, Spolski R, Yu Z, Sanchez-Perez L, Muranski P, Kern SJ, Logun C, Palmer DC, Ji Y, Reger RN, Leonard WJ, Danner RL, Rosenberg SA, Restifo NP (2009) Adoptively transferred effector cells derived from naive rather than central memory CD8 + T cells mediate superior antitumor immunity. Proc Natl Acad Sci USA 106(41):17469–17474. doi:10.1073/pnas.0907448106

    Article  PubMed  CAS  Google Scholar 

  80. Hinrichs CS, Borman ZA, Gattinoni L, Yu Z, Burns WR, Huang J, Klebanoff CA, Johnson LA, Kerkar SP, Yang S, Muranski P, Palmer DC, Scott CD, Morgan RA, Robbins PF, Rosenberg SA, Restifo NP (2011) Human effector CD8 + T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. Blood 117(3):808–814. doi:10.1182/blood-2010-05-286286

    Article  PubMed  CAS  Google Scholar 

  81. Klebanoff CA, Gattinoni L, Palmer DC, Muranski P, Ji Y, Hinrichs CS, Borman ZA, Kerkar SP, Scott CD, Finkelstein SE, Rosenberg SA, Restifo NP (2011) Determinants of successful CD8 + T-cell adoptive immunotherapy for large established tumors in mice. Clin Cancer Res 17(16):5343–5352. doi:10.1158/1078-0432.CCR-11-0503

    Article  PubMed  CAS  Google Scholar 

  82. Yang S, Gattinoni L, Liu F, Ji Y, Yu Z, Restifo NP, Rosenberg SA, Morgan RA (2011) In vitro generated anti-tumor T lymphocytes exhibit distinct subsets mimicking in vivo antigen-experienced cells. Cancer Immunol Immunother 60(5):739–749. doi:10.1007/s00262-011-0977-7

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

DEG, REH, and DGR were funded by Cancer Research UK. This work was also supported by the EU FP6 programme ATTACK, FP7 training Network ATTRACT and the Kay Kendall Leukaemia Fund. The authors also wish to acknowledge Professor Hinrich Abken (University of Cologne) for his critical assessment of this manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Clinical and Experimental Immunotherapy Group, School of Cancer and Enabling Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

    Grazyna Lipowska-Bhalla, David E. Gilham & Robert E. Hawkins

  2. Clinical and Molecular Monitoring Laboratory, Clinical and Experimental Pharmacology Group, Manchester Academic Health Science Centre, School of Cancer and Enabling Sciences, University of Manchester, Manchester, UK

    Grazyna Lipowska-Bhalla & Dominic G. Rothwell

  3. Clinical and Experimental Immunotherapy Group, Paterson Institute for Cancer Research, Wilmslow Road, Withington, Manchester, M20 4BX, UK

    David E. Gilham

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  1. Grazyna Lipowska-Bhalla
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  2. David E. Gilham
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  3. Robert E. Hawkins
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  4. Dominic G. Rothwell
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Correspondence to David E. Gilham.

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Lipowska-Bhalla, G., Gilham, D.E., Hawkins, R.E. et al. Targeted immunotherapy of cancer with CAR T cells: achievements and challenges. Cancer Immunol Immunother 61, 953–962 (2012). https://doi.org/10.1007/s00262-012-1254-0

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  • DOI: https://doi.org/10.1007/s00262-012-1254-0

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