Cellular and Molecular Life Sciences

, Volume 71, Issue 7, pp 1211–1224 | Cite as

Impact of T cell selection methods in the success of clinical adoptive immunotherapy

  • Natalia Ramírez
  • Lorea Beloki
  • Miriam Ciaúrriz
  • Mercedes Rodríguez-Calvillo
  • David Escors
  • Cristina Mansilla
  • Eva Bandrés
  • Eduardo Olavarría


Chemotherapy and/or radiotherapy regular regimens used for conditioning of recipients of hematopoietic stem cell transplantation (SCT) induce a period of transient profound immunosuppression. The onset of a competent immunological response, such as the appearance of viral-specific T cells, is associated with a lower incidence of viral infections after haematopoietic transplantation. The rapid development of immunodominant peptide virus screening together with advances in the design of genetic and non-genetic viral- and tumoural-specific cellular selection strategies have opened new strategies for cellular immunotherapy in oncologic recipients who are highly sensitive to viral infections. However, the rapid development of cellular immunotherapy in SCT has disclosed the role of the T cell selection method in the modulation of functional cell activity and of in vivo secondary effects triggered following immunotherapy.


Cellular immunotherapy Antigen-specific cytotoxic T cells Cellular functional modulation In vitro cellular selection methods Haematopoietic stem cell transplant 

Supplementary material

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Supplementary material 1 (DOC 113 kb)
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Supplementary material 2 (DOC 124 kb)
18_2013_1463_MOESM3_ESM.doc (90 kb)
Supplementary material 3 (DOC 90 kb)
18_2013_1463_MOESM4_ESM.doc (35 kb)
Supplementary material 4 (DOC 35 kb)


  1. 1.
    Zaia J, Baden L, Boeckh MJ, Chakrabarti S, Einsele H, Ljungman P, McDonald GB, Hirsch H (2009) Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transplant 44(8):471–482PubMedGoogle Scholar
  2. 2.
    Winston DJ, Ho WG, Bartoni K, Du Mond C, Ebeling DF, Buhles WC, Champlin RE (1993) Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial. Ann Intern Med 118(3):179–184PubMedGoogle Scholar
  3. 3.
    Bollard CM, Kuehnle I, Leen A, Rooney CM, Heslop HE (2004) Adoptive immunotherapy for posttransplantation viral infections. Biol Blood Marrow Transplant 10(3):143–155PubMedGoogle Scholar
  4. 4.
    Perry AR, Mackinnon S (1996) Adoptive immunotherapy post bone-marrow transplantation. Blood Rev 10(4):237–241PubMedGoogle Scholar
  5. 5.
    Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G, Heim M, Wilmanns W (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76(12):2462–2465PubMedGoogle Scholar
  6. 6.
    Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, Carabasi MH, Castro-Malaspina H, Childs BH, Gillio AP, Small TN et al (1994) Infusions of donor leukocytes to treat Epstein–Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 330(17):1185–1191PubMedGoogle Scholar
  7. 7.
    Heslop HE, Brenner MK, Rooney CM (1994) Donor T cells to treat EBV-associated lymphoma. N Engl J Med 331(10):679–680PubMedGoogle Scholar
  8. 8.
    Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D, van Rhee F, Mittermueller J, de Witte T, Holler E, Ansari H (1995) Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86(5):2041–2050PubMedGoogle Scholar
  9. 9.
    Lanzavecchia A, Sallusto F (2002) Progressive differentiation and selection of the fittest in the immune response. Nat Rev Immunol 2(12):982–987PubMedGoogle Scholar
  10. 10.
    Kaech SM, Wherry EJ, Ahmed R (2002) Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2(4):251–262PubMedGoogle Scholar
  11. 11.
    Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, von Andrian UH, Ahmed R (2003) Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 4(3):225–234PubMedGoogle Scholar
  12. 12.
    Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257(5067):238–241PubMedGoogle Scholar
  13. 13.
    Riddell SR, Rabin M, Geballe AP, Britt WJ, Greenberg PD (1991) Class I MHC-restricted cytotoxic T lymphocyte recognition of cells infected with human cytomegalovirus does not require endogenous viral gene expression. J Immunol 146(8):2795–2804PubMedGoogle Scholar
  14. 14.
    Peggs K, Verfuerth S, Mackinnon S (2001) Induction of cytomegalovirus (CMV)-specific T-cell responses using dendritic cells pulsed with CMV antigen: a novel culture system free of live CMV virions. Blood 97(4):994–1000PubMedGoogle Scholar
  15. 15.
    Doubrovina E, Oflaz-Sozmen B, Prockop SE, Kernan NA, Abramson S, Teruya-Feldstein J, Hedvat C, Chou JF, Heller G, Barker JN, Boulad F, Castro-Malaspina H, George D, Jakubowski A, Koehne G, Papadopoulos EB, Scaradavou A, Small TN, Khalaf R, Young JW, O’Reilly RJ (2012) Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood 119(11):2644–2656PubMedCentralPubMedGoogle Scholar
  16. 16.
    Peggs KS, Thomson K, Samuel E, Dyer G, Armoogum J, Chakraverty R, Pang K, Mackinnon S, Lowdell MW (2011) Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Clin Infect Dis 52(1):49–57PubMedGoogle Scholar
  17. 17.
    Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, Bollard CM, Liu H, Wu MF, Rochester RJ, Amrolia PJ, Hurwitz JL, Brenner MK, Rooney CM (2010) Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115(5):925–935PubMedCentralPubMedGoogle Scholar
  18. 18.
    Melenhorst JJ, Leen AM, Bollard CM, Quigley MF, Price DA, Rooney CM, Brenner MK, Barrett AJ, Heslop HE (2010) Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects. Blood 116(22):4700–4702PubMedCentralPubMedGoogle Scholar
  19. 19.
    Wang Q, Liu H, Zhang X, Liu Q, Xing Y, Zhou X, Tong C, Zhu P (2010) High doses of mother’s lymphocyte infusion to treat EBV-positive T-cell lymphoproliferative disorders in childhood. Blood 116(26):5941–5947PubMedGoogle Scholar
  20. 20.
    Jones K, Nourse JP, Morrison L, Nguyen-Van D, Moss DJ, Burrows SR, Gandhi MK (2010) Expansion of EBNA1-specific effector T cells in posttransplantation lymphoproliferative disorders. Blood 116(13):2245–2252PubMedGoogle Scholar
  21. 21.
    Scheinberg P, Melenhorst JJ, Brenchley JM, Hill BJ, Hensel NF, Chattopadhyay PK, Roederer M, Picker LJ, Price DA, Barrett AJ, Douek DC (2009) The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor. Blood 114(24):5071–5080PubMedCentralPubMedGoogle Scholar
  22. 22.
    Peggs KS, Verfuerth S, Pizzey A, Chow SL, Thomson K, Mackinnon S (2009) Cytomegalovirus-specific T cell immunotherapy promotes restoration of durable functional antiviral immunity following allogeneic stem cell transplantation. Clin Infect Dis 49(12):1851–1860PubMedGoogle Scholar
  23. 23.
    Brestrich G, Zwinger S, Fischer A, Schmuck M, Rohmhild A, Hammer MH, Kurtz A, Uharek L, Knosalla C, Lehmkuhl H, Volk HD, Reinke P (2009) Adoptive T-cell therapy of a lung transplanted patient with severe CMV disease and resistance to antiviral therapy. Am J Transplant 9(7):1679–1684PubMedGoogle Scholar
  24. 24.
    Hill GR, Tey SK, Beagley L, Crough T, Morton JA, Clouston AD, Whiting P, Khanna R (2009) Successful immunotherapy of HCMV disease using virus-specific T cells expanded from an allogeneic stem cell transplant recipient. Am J Transplant 10(1):173–179PubMedGoogle Scholar
  25. 25.
    Ohira M, Ishiyama K, Tanaka Y, Doskali M, Igarashi Y, Tashiro H, Hiraga N, Imamura M, Sakamoto N, Asahara T, Chayama K, Ohdan H (2009) Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice. J Clin Invest 119(11):3226–3235PubMedCentralPubMedGoogle Scholar
  26. 26.
    Leen AM, Christin A, Myers GD, Liu H, Cruz CR, Hanley PJ, Kennedy-Nasser AA, Leung KS, Gee AP, Krance RA, Brenner MK, Heslop HE, Rooney CM, Bollard CM (2009) Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein–Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood 114(19):4283–4292PubMedCentralPubMedGoogle Scholar
  27. 27.
    Louis CU, Straathof K, Bollard CM, Gerken C, Huls MH, Gresik MV, Wu MF, Weiss HL, Gee AP, Brenner MK, Rooney CM, Heslop HE, Gottschalk S (2009) Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients. Blood 113(11):2442–2450PubMedCentralPubMedGoogle Scholar
  28. 28.
    Micklethwaite KP, Clancy L, Sandher U, Hansen AM, Blyth E, Antonenas V, Sartor MM, Bradstock KF, Gottlieb DJ (2008) Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp 65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation. Blood 112(10):3974–3981PubMedGoogle Scholar
  29. 29.
    Bollard CM, Gottschalk S, Leen AM, Weiss H, Straathof KC, Carrum G, Khalil M, Wu MF, Huls MH, Chang CC, Gresik MV, Gee AP, Brenner MK, Rooney CM, Heslop HE (2007) Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood 110(8):2838–2845PubMedCentralPubMedGoogle Scholar
  30. 30.
    Gandhi MK, Wilkie GM, Dua U, Mollee PN, Grimmett K, Williams T, Whitaker N, Gill D, Crawford DH (2007) Immunity, homing and efficacy of allogeneic adoptive immunotherapy for posttransplant lymphoproliferative disorders. Am J Transplant 7(5):1293–1299PubMedGoogle Scholar
  31. 31.
    Haque T, Wilkie GM, Jones MM, Higgins CD, Urquhart G, Wingate P, Burns D, McAulay K, Turner M, Bellamy C, Amlot PL, Kelly D, MacGilchrist A, Gandhi MK, Swerdlow AJ, Crawford DH (2007) Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood 110(4):1123–1131PubMedGoogle Scholar
  32. 32.
    Amrolia PJ, Muccioli-Casadei G, Huls H, Adams S, Durett A, Gee A, Yvon E, Weiss H, Cobbold M, Gaspar HB, Rooney C, Kuehnle I, Ghetie V, Schindler J, Krance R, Heslop HE, Veys P, Vitetta E, Brenner MK (2006) Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 108(6):1797–1808PubMedCentralPubMedGoogle Scholar
  33. 33.
    Perruccio K, Tosti A, Burchielli E, Topini F, Ruggeri L, Carotti A, Capanni M, Urbani E, Mancusi A, Aversa F, Martelli MF, Romani L, Velardi A (2005) Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood 106(13):4397–4406PubMedCentralPubMedGoogle Scholar
  34. 34.
    Comoli P, Pedrazzoli P, Maccario R, Basso S, Carminati O, Labirio M, Schiavo R, Secondino S, Frasson C, Perotti C, Moroni M, Locatelli F, Siena S (2005) Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein–Barr virus-targeted cytotoxic T lymphocytes. J Clin Oncol 23(35):8942–8949PubMedGoogle Scholar
  35. 35.
    Bollard CM, Aguilar L, Straathof KC, Gahn B, Huls MH, Rousseau A, Sixbey J, Gresik MV, Carrum G, Hudson M, Dilloo D, Gee A, Brenner MK, Rooney CM, Heslop HE (2004) Cytotoxic T lymphocyte therapy for Epstein–Barr virus+ Hodgkin’s disease. J Exp Med 200(12):1623–1633PubMedCentralPubMedGoogle Scholar
  36. 36.
    Einsele H, Roosnek E, Rufer N, Sinzger C, Riegler S, Loffler J, Grigoleit U, Moris A, Rammensee HG, Kanz L, Kleihauer A, Frank F, Jahn G, Hebart H (2002) Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood 99(11):3916–3922PubMedGoogle Scholar
  37. 37.
    Savoldo B, Huls MH, Liu Z, Okamura T, Volk HD, Reinke P, Sabat R, Babel N, Jones JF, Webster-Cyriaque J, Gee AP, Brenner MK, Heslop HE, Rooney CM (2002) Autologous Epstein–Barr virus (EBV)-specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood 100(12):4059–4066PubMedGoogle Scholar
  38. 38.
    Lin CL, Lo WF, Lee TH, Ren Y, Hwang SL, Cheng YF, Chen CL, Chang YS, Lee SP, Rickinson AB, Tam PK (2002) Immunization with Epstein–Barr Virus (EBV) peptide-pulsed dendritic cells induces functional CD8+ T-cell immunity and may lead to tumor regression in patients with EBV-positive nasopharyngeal carcinoma. Cancer Res 62(23):6952–6958PubMedGoogle Scholar
  39. 39.
    Haque T, Wilkie GM, Taylor C, Amlot PL, Murad P, Iley A, Dombagoda D, Britton KM, Swerdlow AJ, Crawford DH (2002) Treatment of Epstein–Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet 360(9331):436–442PubMedGoogle Scholar
  40. 40.
    Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, Bakker A, Roberts MR, June CH, Jalali S, Lin AA, Pennathur-Das R, Hege KM (2000) Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood 96(3):785–793PubMedGoogle Scholar
  41. 41.
    Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiarski J, Ernberg I, Masucci MG (2000) Epstein–Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood 95(3):807–814PubMedGoogle Scholar
  42. 42.
    Small TN, Papadopoulos EB, Boulad F, Black P, Castro-Malaspina H, Childs BH, Collins N, Gillio A, George D, Jakubowski A, Heller G, Fazzari M, Kernan N, MacKinnon S, Szabolcs P, Young JW, O’Reilly RJ (1999) Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 93(2):467–480PubMedGoogle Scholar
  43. 43.
    Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y, Srivastava DK, Bowman LC, Krance RA, Brenner MK, Heslop HE (1998) Infusion of cytotoxic T cells for the prevention and treatment of Epstein–Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92(5):1549–1555PubMedGoogle Scholar
  44. 44.
    Rooney CM, Roskrow MA, Smith CA, Brenner MK, Heslop HE (1998) Immunotherapy for Epstein–Barr virus-associated cancers. J Natl Cancer Inst Monogr 23:89–93PubMedGoogle Scholar
  45. 45.
    Roskrow MA, Suzuki N, Gan Y, Sixbey JW, Ng CY, Kimbrough S, Hudson M, Brenner MK, Heslop HE, Rooney CM (1998) Epstein–Barr virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin’s disease. Blood 91(8):2925–2934PubMedGoogle Scholar
  46. 46.
    O’Reilly RJ, Small TN, Papadopoulos E, Lucas K, Lacerda J, Koulova L (1997) Biology and adoptive cell therapy of Epstein–Barr virus-associated lymphoproliferative disorders in recipients of marrow allografts. Immunol Rev 157:195–216PubMedGoogle Scholar
  47. 47.
    Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA, Brenner MK, Heslop HE (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein–Barr-virus-related lymphoproliferation. Lancet 345(8941):9–13PubMedGoogle Scholar
  48. 48.
    Bex F, Hermans P, Sprecher S, Achour A, Badjou R, Desgranges C, Cogniaux J, Franchioli P, Vanhulle C, Lachgar A et al (1994) Syngeneic adoptive transfer of anti-human immunodeficiency virus (HIV-1)-primed lymphocytes from a vaccinated HIV-seronegative individual to his HIV-1-infected identical twin. Blood 84(10):3317–3326PubMedGoogle Scholar
  49. 49.
    Ho M, Armstrong J, McMahon D, Pazin G, Huang XL, Rinaldo C, Whiteside T, Tripoli C, Levine G, Moody D et al (1993) A phase 1 study of adoptive transfer of autologous CD8+ T lymphocytes in patients with acquired immunodeficiency syndrome (AIDS)-related complex or AIDS. Blood 81(8):2093–2101PubMedGoogle Scholar
  50. 50.
    Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333(16):1038–1044PubMedGoogle Scholar
  51. 51.
    Heslop HE, Ng CY, Li C, Smith CA, Loftin SK, Krance RA, Brenner MK, Rooney CM (1996) Long-term restoration of immunity against Epstein–Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med 2(5):551–555PubMedGoogle Scholar
  52. 52.
    Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, Mackinnon S (2003) Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 362(9393):1375–1377PubMedGoogle Scholar
  53. 53.
    Liechtenstein T, Dufait I, Lanna A, Breckpot K, Escors D (2013) Modulating co-stimulation during antigen presentation to enhance cancer immunotherapy. Immunol Endocr Metab Agents Med Chem 12(3):224–235Google Scholar
  54. 54.
    Sun Q, Pollok KE, Burton RL, Dai LJ, Britt W, Emanuel DJ, Lucas KG (1999) Simultaneous ex vivo expansion of cytomegalovirus and Epstein–Barr virus-specific cytotoxic T lymphocytes using B-lymphoblastoid cell lines expressing cytomegalovirus pp 65. Blood 94(9):3242–3250PubMedGoogle Scholar
  55. 55.
    Leen AM, Myers GD, Sili U, Huls MH, Weiss H, Leung KS, Carrum G, Krance RA, Chang CC, Molldrem JJ, Gee AP, Brenner MK, Heslop HE, Rooney CM, Bollard CM (2006) Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med 12(10):1160–1166PubMedGoogle Scholar
  56. 56.
    Dembic Z, Haas W, Weiss S, McCubrey J, Kiefer H, von Boehmer H, Steinmetz M (1986) Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320(6059):232–238PubMedGoogle Scholar
  57. 57.
    Gehring AJ, Xue SA, Ho ZZ, Teoh D, Ruedl C, Chia A, Koh S, Lim SG, Maini MK, Stauss H, Bertoletti A (2011) Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J Hepatol 55(1):103–110PubMedGoogle Scholar
  58. 58.
    Wood NJ (2011) Immunotherapy: therapeutic potential of genetically modified HBV-specific T cells for chronic HBV infection and HBV-related HCC. Nat Rev 8(2):61Google Scholar
  59. 59.
    Kessels HW, Wolkers MC, van den Boom MD, van der Valk MA, Schumacher TN (2001) Immunotherapy through TCR gene transfer. Nat Immunol 2(10):957–961PubMedGoogle Scholar
  60. 60.
    Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, Kammula US, Royal RE, Sherry RM, Wunderlich JR, Lee CC, Restifo NP, Schwarz SL, Cogdill AP, Bishop RJ, Kim H, Brewer CC, Rudy SF, VanWaes C, Davis JL, Mathur A, Ripley RT, Nathan DA, Laurencot CM, Rosenberg SA (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114(3):535–546PubMedCentralPubMedGoogle Scholar
  61. 61.
    Heemskerk MH, Hoogeboom M, Hagedoorn R, Kester MG, Willemze R, Falkenburg JH (2004) Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer. J Exp Med 199(7):885–894PubMedCentralPubMedGoogle Scholar
  62. 62.
    Cohen CJ, Li YF, El-Gamil M, Robbins PF, Rosenberg SA, Morgan RA (2007) Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. Cancer Res 67(8):3898–3903PubMedCentralPubMedGoogle Scholar
  63. 63.
    Cohen CJ, Zhao Y, Zheng Z, Rosenberg SA, Morgan RA (2006) Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res 66(17):8878–8886PubMedCentralPubMedGoogle Scholar
  64. 64.
    Bialer G, Horovitz-Fried M, Ya’acobi S, Morgan RA, Cohen CJ (2010) Selected murine residues endow human TCR with enhanced tumor recognition. J Immunol 184(11):6232–6241PubMedGoogle Scholar
  65. 65.
    Kandalaft LE, Powell DJ Jr, Coukos G (2012) A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. J Transl Med 10:157PubMedCentralPubMedGoogle Scholar
  66. 66.
    Brenner MK, Heslop HE (2010) Adoptive T cell therapy of cancer. Curr Opin Immunol 22(2):251–257PubMedCentralPubMedGoogle Scholar
  67. 67.
    Jena B, Dotti G, Cooper LJ (2010) Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. Blood 116(7):1035–1044PubMedCentralPubMedGoogle Scholar
  68. 68.
    Micklethwaite KP, Savoldo B, Hanley PJ, Leen AM, Demmler-Harrison GJ, Cooper LJ, Liu H, Gee AP, Shpall EJ, Rooney CM, Heslop HE, Brenner MK, Bollard CM, Dotti G (2010) Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation. Blood 115(13):2695–2703PubMedCentralPubMedGoogle Scholar
  69. 69.
    De Oliveira SN, Wang J, Ryan C, Morrison SL, Kohn DB, Hollis RP (2013) A CD19/Fc fusion protein for detection of anti-CD19 chimeric antigen receptors. J Transl Med 11(1):23PubMedCentralPubMedGoogle Scholar
  70. 70.
    Tamada K, Geng D, Sakoda Y, Bansal N, Srivastava R, Li Z, Davila E (2012) Redirecting gene-modified T cells toward various cancer types using tagged antibodies. Clin Cancer Res 18(23):6436–6445PubMedGoogle Scholar
  71. 71.
    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 118(23):6050–6056PubMedCentralPubMedGoogle Scholar
  72. 72.
    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):1264–1270PubMedCentralPubMedGoogle Scholar
  73. 73.
    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):6106–6115PubMedCentralPubMedGoogle Scholar
  74. 74.
    Shi H, Liu L, Wang Z (2013) Improving the efficacy and safety of engineered T cell therapy for cancer. Cancer Lett 328(2):191–197PubMedGoogle Scholar
  75. 75.
    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 signalling through CD137 (4-1BB). Cancer Res 71(13):4617–4627PubMedGoogle Scholar
  76. 76.
    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):95ra73PubMedCentralPubMedGoogle Scholar
  77. 77.
    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):725–733PubMedCentralPubMedGoogle Scholar
  78. 78.
    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):666–668PubMedCentralPubMedGoogle Scholar
  79. 79.
    Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518PubMedGoogle Scholar
  80. 80.
    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):843–851PubMedCentralPubMedGoogle Scholar
  81. 81.
    Heslop HE (2010) Safer CARS. Mol Ther 18(4):661–662PubMedCentralPubMedGoogle Scholar
  82. 82.
    Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Mavilio F, Traversari C, Bordignon C (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276(5319):1719–1724PubMedGoogle Scholar
  83. 83.
    Ciceri F, Bonini C, Marktel S, Zappone E, Servida P, Bernardi M, Pescarollo A, Bondanza A, Peccatori J, Rossini S, Magnani Z, Salomoni M, Benati C, Ponzoni M, Callegaro L, Corradini P, Bregni M, Traversari C, Bordignon C (2007) Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation. Blood 109(11):4698–4707PubMedGoogle Scholar
  84. 84.
    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):489–500PubMedGoogle Scholar
  85. 85.
    Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK (2011) Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 365(18):1673–1683PubMedCentralPubMedGoogle Scholar
  86. 86.
    Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM (2005) An inducible caspase 9 safety switch for T-cell therapy. Blood 105(11):4247–4254PubMedCentralPubMedGoogle Scholar
  87. 87.
    Tey SK, Dotti G, Rooney CM, Heslop HE, Brenner MK (2007) Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biol Blood Marrow Transplant 13(8):913–924PubMedCentralPubMedGoogle Scholar
  88. 88.
    Quintarelli C, Vera JF, Savoldo B, Giordano Attianese GM, Pule M, Foster AE, Heslop HE, Rooney CM, Brenner MK, Dotti G (2007) Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes. Blood 110(8):2793–2802PubMedCentralPubMedGoogle Scholar
  89. 89.
    Ramirez N, Olavarria E (2013) Viral-specific adoptive immunotherapy after allo-SCT: the role of multimer-based selection strategies. Bone Marrow Transplant. doi:10.1038/bmt.2012.262 [Epub ahead of print]
  90. 90.
    Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman H, Assenmacher M, Billingham L, Steward C, Crawley C, Olavarria E, Goldman J, Chakraverty R, Mahendra P, Craddock C, Moss PA (2005) Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med 202(3):379–386PubMedCentralPubMedGoogle Scholar
  91. 91.
    Uhlin M, Okas M, Gertow J, Uzunel M, Brismar TB, Mattsson J (2009) A novel haplo-identical adoptive CTL therapy as a treatment for EBV-associated lymphoma after stem cell transplantation. Cancer Immunol Immunother 59(3):473–477PubMedGoogle Scholar
  92. 92.
    Casalegno-Garduno R, Schmitt A, Yao J, Wang X, Xu X, Freund M, Schmitt M (2010) Multimer technologies for detection and adoptive transfer of antigen-specific T cells. Cancer Immunol Immunother 59(2):195–202PubMedGoogle Scholar
  93. 93.
    Morita-Hoshi Y, Heike Y, Kawakami M, Sugita T, Miura O, Kim SW, Mori SI, Fukuda T, Tanosaki R, Tobinai K, Takaue Y (2008) Functional analysis of cytomegalovirus-specific T lymphocytes compared to tetramer assay in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 41(6):515–521PubMedGoogle Scholar
  94. 94.
    Assenmacher M, Scheffold A, Schmitz J, Segura Checa JA, Miltenyi S, Radbruch A (1996) Specific expression of surface interferon-gamma on interferon-gamma producing T cells from mouse and man. Eur J Immunol 26(1):263–267PubMedGoogle Scholar
  95. 95.
    Manz R, Assenmacher M, Pfluger E, Miltenyi S, Radbruch A (1995) Analysis and sorting of live cells according to secreted molecules, relocated to a cell-surface affinity matrix. Proc Natl Acad Sci USA 92(6):1921–1925PubMedCentralPubMedGoogle Scholar
  96. 96.
    Assenmacher M, Lohning M, Scheffold A, Manz RA, Schmitz J, Radbruch A (1998) Sequential production of IL-2, IFN-gamma and IL-10 by individual staphylococcal enterotoxin B-activated T helper lymphocytes. Eur J Immunol 28(5):1534–1543PubMedGoogle Scholar
  97. 97.
    Moosmann A, Bigalke I, Tischer J, Schirrmann L, Kasten J, Tippmer S, Leeping M, Prevalsek D, Jaeger G, Ledderose G, Mautner J, Hammerschmidt W, Schendel DJ, Kolb HJ (2010) Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells. Blood 115(14):2960–2970PubMedGoogle Scholar
  98. 98.
    Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger EM, Mohty M, Or R, Maschan M, Schumm M, Hamprecht K, Handgretinger R, Lang P, Einsele H (2010) Adoptive transfer of pp 65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 116(20):4360–4367PubMedGoogle Scholar
  99. 99.
    Brosterhus H, Brings S, Leyendeckers H, Manz RA, Miltenyi S, Radbruch A, Assenmacher M, Schmitz J (1999) Enrichment and detection of live antigen-specific CD4(+) and CD8(+) T cells based on cytokine secretion. Eur J Immunol 29(12):4053–4059PubMedGoogle Scholar
  100. 100.
    Desombere I, Meuleman P, Rigole H, Willems A, Irsch J, Leroux-Roels G (2004) The interferon gamma secretion assay: a reliable tool to study interferon gamma production at the single cell level. J Immunol Methods 286(1–2):167–185PubMedGoogle Scholar
  101. 101.
    Jedema I, Meij P, Steeneveld E, Hoogendoorn M, Nijmeijer BA, van de Meent M, van Luxemburg-Heijs SA, Willemze R, Falkenburg JH (2007) Early detection and rapid isolation of leukemia-reactive donor T cells for adoptive transfer using the IFN-gamma secretion assay. Clin Cancer Res 13(2 Pt 1):636–643PubMedGoogle Scholar
  102. 102.
    Mutis T, Gillespie G, Schrama E, Falkenburg JH, Moss P, Goulmy E (1999) Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat Med 5(7):839–842PubMedGoogle Scholar
  103. 103.
    Wang X, Schmitt A, Chen B, Xu X, Mani J, Linnebacher M, Freund M, Schmitt M (2010) Streptamer-based selection of WT1-specific CD8+ T cells for specific donor lymphocyte infusions. Exp Hematol 38(11):1066–1073PubMedGoogle Scholar
  104. 104.
    Kohn DB, Dotti G, Brentjens R, Savoldo B, Jensen M, Cooper LJ, June CH, Rosenberg S, Sadelain M, Heslop HE (2011) CARs on track in the clinic. Mol Ther 19(3):432–438PubMedCentralPubMedGoogle Scholar
  105. 105.
    Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, Finkelstein SE, Theoret MR, Rosenberg SA, Restifo NP (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 115(6):1616–1626PubMedCentralPubMedGoogle Scholar
  106. 106.
    Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR (2008) Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118(1):294–305PubMedCentralPubMedGoogle Scholar
  107. 107.
    Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22:745–763PubMedGoogle Scholar
  108. 108.
    Fiorenza S, Kenna TJ, Comerford I, McColl S, Steptoe RJ, Leggatt GR, Frazer IH (2012) A combination of local inflammation and central memory T cells potentiates immunotherapy in the skin. J Immunol 189(12):5622–5631PubMedCentralPubMedGoogle Scholar
  109. 109.
    Wang X, Naranjo A, Brown CE, Bautista C, Wong CW, Chang WC, Aguilar B, Ostberg JR, Riddell SR, Forman SJ, Jensen MC (2012) Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale. J Immunother 35(9):689–701PubMedCentralPubMedGoogle Scholar
  110. 110.
    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):72–82PubMedCentralPubMedGoogle Scholar
  111. 111.
    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):17469–17474PubMedCentralPubMedGoogle Scholar
  112. 112.
    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):808–814PubMedCentralPubMedGoogle Scholar
  113. 113.
    Hanley PJ, Cruz CR, Savoldo B, Leen AM, Stanojevic M, Khalil M, Decker W, Molldrem JJ, Liu H, Gee AP, Rooney CM, Heslop HE, Dotti G, Brenner MK, Shpall EJ, Bollard CM (2009) Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood 114(9):1958–1967PubMedCentralPubMedGoogle Scholar
  114. 114.
    Distler E, Wolfel C, Kohler S, Nonn M, Kaus N, Schnurer E, Meyer RG, Wehler TC, Huber C, Wolfel T, Hartwig UF, Herr W (2008) Acute myeloid leukemia (AML)-reactive cytotoxic T lymphocyte clones rapidly expanded from CD8(+) CD62L((high)+) T cells of healthy donors prevent AML engraftment in NOD/SCID IL2Rgamma(null) mice. Exp Hematol 36(4):451–463PubMedGoogle Scholar
  115. 115.
    Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6(5):383–393PubMedCentralPubMedGoogle Scholar
  116. 116.
    Speiser DE, Romero P (2005) Toward improved immunocompetence of adoptively transferred CD8+ T cells. J Clin Invest 115(6):1467–1469PubMedCentralPubMedGoogle Scholar
  117. 117.
    Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ, Shlomchik WD (2003) Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest 112(1):101–108PubMedCentralPubMedGoogle Scholar
  118. 118.
    Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB, Herman EI, Baker EM, Cao YA, Contag CH, Negrin RS (2005) In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 106(3):1113–1122PubMedCentralPubMedGoogle Scholar
  119. 119.
    Distler E, Bloetz A, Albrecht J, Asdufan S, Hohberger A, Frey M, Schnurer E, Thomas S, Theobald M, Hartwig UF, Herr W (2011) Alloreactive and leukemia-reactive T cells are preferentially derived from naive precursors in healthy donors: implications for immunotherapy with memory T cells. Haematologica 96(7):1024–1032PubMedCentralPubMedGoogle Scholar
  120. 120.
    Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzesinski C, Boni A, Cassard L, Garvin LM, Paulos CM, Muranski P, Restifo NP (2009) Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 15(7):808–813PubMedCentralPubMedGoogle Scholar
  121. 121.
    Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, Restifo NP (2011) A human memory T cell subset with stem cell-like properties. Nat Med 17(10):1290–1297PubMedCentralPubMedGoogle Scholar
  122. 122.
    Sallusto F, Lanzavecchia A (2011) Memory in disguise. Nat Med 17(10):1182–1183PubMedGoogle Scholar
  123. 123.
    Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 202(7):907–912PubMedCentralPubMedGoogle Scholar
  124. 124.
    Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594):850–854PubMedCentralPubMedGoogle Scholar
  125. 125.
    Jacobs SR, Michalek RD, Rathmell JC (2010) IL-7 is essential for homeostatic control of T cell metabolism in vivo. J Immunol 184(7):3461–3469PubMedCentralPubMedGoogle Scholar
  126. 126.
    Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26(32):5233–5239PubMedCentralPubMedGoogle Scholar
  127. 127.
    Muranski P, Boni A, Wrzesinski C, Citrin DE, Rosenberg SA, Childs R, Restifo NP (2006) Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? Nat Clin Pract Oncol 3(12):668–681PubMedCentralPubMedGoogle Scholar
  128. 128.
    Brusko TM, Putnam AL, Bluestone JA (2008) Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 223:371–390PubMedGoogle Scholar
  129. 129.
    Morita R, Hirohashi Y, Sato N (2012) Depletion of Tregs in vivo: a promising approach to enhance antitumor immunity without autoimmunity. Immunotherapy 4(11):1103–1105PubMedGoogle Scholar
  130. 130.
    Rech AJ, Mick R, Martin S, Recio A, Aqui NA, Powell DJ Jr, Colligon TA, Trosko JA, Leinbach LI, Pletcher CH, Tweed CK, DeMichele A, Fox KR, Domchek SM, Riley JL, Vonderheide RH (2012) CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med 4(134):134ra162Google Scholar
  131. 131.
    Unutmaz D, Pileri P, Abrignani S (1994) Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J Exp Med 180(3):1159–1164PubMedGoogle Scholar
  132. 132.
    Buentke E, Mathiot A, Tolaini M, Di Santo J, Zamoyska R, Seddon B (2006) Do CD8 effector cells need IL-7R expression to become resting memory cells? Blood 108(6):1949–1956PubMedGoogle Scholar
  133. 133.
    Shen CH, Ge Q, Talay O, Eisen HN, Garcia-Sastre A, Chen J (2008) Loss of IL-7R and IL-15R expression is associated with disappearance of memory T cells in respiratory tract following influenza infection. J Immunol 180(1):171–178PubMedCentralPubMedGoogle Scholar
  134. 134.
    Mackall C, Fry T, Gress R, Peggs K, Storek J, Toubert A (2009) Background to hematopoietic cell transplantation, including post transplant immune recovery. Bone Marrow Transplant 44(8):457–462PubMedGoogle Scholar
  135. 135.
    Hakki M, Riddell SR, Storek J, Carter RA, Stevens-Ayers T, Sudour P, White K, Corey L, Boeckh M (2003) Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood 102(8):3060–3067PubMedGoogle Scholar
  136. 136.
    Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD (1997) Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278(5342):1447–1450PubMedGoogle Scholar
  137. 137.
    Teramoto K, Ohshio Y, Fujita T, Hanaoka J, Kontani K (2013) Simultaneous activation of T helper function can augment the potency of dendritic cell-based cancer immunotherapy. J Cancer Res Clin Oncol 139(5):861–870PubMedGoogle Scholar
  138. 138.
    Ayyoub M, Dojcinovic D, Pignon P, Raimbaud I, Schmidt J, Luescher I, Valmori D (2010) Monitoring of NY-ESO-1 specific CD4+ T cells using molecularly defined MHC class II/His-tag-peptide tetramers. Proc Natl Acad Sci USA 107(16):7437–7442PubMedCentralPubMedGoogle Scholar
  139. 139.
    Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, Blasberg R, Yagita H, Muranski P, Antony PA, Restifo NP, Allison JP (2010) Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 207(3):637–650PubMedCentralPubMedGoogle Scholar
  140. 140.
    Vanasek TL, Nandiwada SL, Jenkins MK, Mueller DL (2006) CD25+ Foxp3+ regulatory T cells facilitate CD4+ T cell clonal anergy induction during the recovery from lymphopenia. J Immunol 176(10):5880–5889PubMedGoogle Scholar
  141. 141.
    Tanchot C, Le Campion A, Leaument S, Dautigny N, Lucas B (2001) Naive CD4(+) lymphocytes convert to anergic or memory-like cells in T cell-deprived recipients. Eur J Immunol 31(8):2256–2265PubMedGoogle Scholar
  142. 142.
    Reagan JL, Fast LD, Safran H, Nevola M, Winer ES, Castillo JJ, Butera JN, Quesenberry MI, Young CT, Quesenberry PJ (2013) Cellular immunotherapy for refractory hematological malignancies. J Transl Med 11:150PubMedCentralPubMedGoogle Scholar
  143. 143.
    Sato T, Ikeda M, Yotsumoto S, Shimada Y, Higuchi T, Kobayashi H, Fukuda T, Ohashi T, Suda T, Ohteki T (2013) Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder. Blood 121(16):3267–3273PubMedGoogle Scholar
  144. 144.
    Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274(5284):94–96PubMedGoogle Scholar
  145. 145.
    Maile R, Wang B, Schooler W, Meyer A, Collins EJ, Frelinger JA (2001) Antigen-specific modulation of an immune response by in vivo administration of soluble MHC class I tetramers. J Immunol 167(7):3708–3714PubMedGoogle Scholar
  146. 146.
    Neudorfer J, Schmidt B, Huster KM, Anderl F, Schiemann M, Holzapfel G, Schmidt T, Germeroth L, Wagner H, Peschel C, Busch DH, Bernhard H (2007) Reversible HLA multimers (Streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens. J Immunol Methods 320(1–2):119–131PubMedGoogle Scholar
  147. 147.
    Daniels MA, Jameson SC (2000) Critical role for CD8 in T cell receptor binding and activation by peptide/major histocompatibility complex multimers. J Exp Med 191(2):335–346PubMedCentralPubMedGoogle Scholar
  148. 148.
    O’Herrin SM, Slansky JE, Tang Q, Markiewicz MA, Gajewski TF, Pardoll DM, Schneck JP, Bluestone JA (2001) Antigen-specific blockade of T cells in vivo using dimeric MHC peptide. J Immunol 167(5):2555–2560PubMedGoogle Scholar
  149. 149.
    Knabel M, Franz TJ, Schiemann M, Wulf A, Villmow B, Schmidt B, Bernhard H, Wagner H, Busch DH (2002) Reversible MHC multimer staining for functional isolation of T-cell populations and effective adoptive transfer. Nat Med 8(6):631–637PubMedGoogle Scholar
  150. 150.
    Brown IE, Blank C, Kline J, Kacha AK, Gajewski TF (2006) Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J Immunol 177(7):4521–4529PubMedGoogle Scholar
  151. 151.
    Teague RM, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan X, Sutton SE, Cooke MP, Ohlen C, Greenberg PD (2006) Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med 12(3):335–341PubMedGoogle Scholar
  152. 152.
    Wang X, Simeoni L, Lindquist JA, Saez-Rodriguez J, Ambach A, Gilles ED, Kliche S, Schraven B (2008) Dynamics of proximal signaling events after TCR/CD8-mediated induction of proliferation or apoptosis in mature CD8+ T cells. J Immunol 180(10):6703–6712PubMedGoogle Scholar
  153. 153.
    Schmitt A, Tonn T, Busch DH, Grigoleit GU, Einsele H, Odendahl M, Germeroth L, Ringhoffer M, Ringhoffer S, Wiesneth M, Greiner J, Michel D, Mertens T, Rojewski M, Marx M, von Harsdorf S, Dohner H, Seifried E, Bunjes D, Schmitt M (2010) Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus-specific CD8+ T cells leads to virus clearance in patients after allogeneic peripheral blood stem cell transplantation. Transfusion 51(3):591–599PubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Natalia Ramírez
    • 1
  • Lorea Beloki
    • 1
  • Miriam Ciaúrriz
    • 1
  • Mercedes Rodríguez-Calvillo
    • 2
  • David Escors
    • 3
  • Cristina Mansilla
    • 1
  • Eva Bandrés
    • 4
  • Eduardo Olavarría
    • 1
    • 2
  1. 1.Oncohematology Research GroupNavarrabiomed, Miguel Servet FoundationPamplonaSpain
  2. 2.Department of HaematologyComplejo Hospitalario de Navarra, Navarra Health ServicePamplonaSpain
  3. 3.Immunomodulation Research GroupNavarrabiomed, Miguel Servet FoundationPamplonaSpain
  4. 4.Immunology UnitComplejo Hospitalario de Navarra, Navarra Health ServicePamplonaSpain

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