Oncology Reviews

, Volume 4, Issue 4, pp 211–218

Vγ9Vδ2 T cells as a promising innovative tool for immunotherapy of hematologic malignancies

  • Serena Meraviglia
  • Carmela La Mendola
  • Valentina Orlando
  • Francesco Scarpa
  • Giuseppe Cicero
  • Francesco Dieli
Review

Abstract

The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with hematologic malignancies.

Keywords

Vγ9Vδ2 T cells Hematologic malignancies Immunotherapy Cytokines Cytotoxicity 

References

  1. 1.
    Cesco-Gaspere M, Morris E, Stauss HJ (2009) Immunomodulation in the treatment of haematological malignancies. Clin Exp Med 9:81–92CrossRefPubMedGoogle Scholar
  2. 2.
    Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFN-gamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111CrossRefPubMedGoogle Scholar
  3. 3.
    Zittoun RA, Mandelli F, Willemze R et al (1995) Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 332:217–223CrossRefPubMedGoogle Scholar
  4. 4.
    Dudley ME, Wunderlich J, Nishimura MI et al (2001) Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 24:363–373CrossRefPubMedGoogle Scholar
  5. 5.
    Dudley ME, Wunderlich JR, Robbins PF et al (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854CrossRefPubMedGoogle Scholar
  6. 6.
    Falkenburg JH, Wafelman AR, Joosten P et al (1999) Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. Blood 94:1201–1208PubMedGoogle Scholar
  7. 7.
    Marijt E, Wafelman A, van der Hoorn M et al (2007) Phase I/II feasibility study evaluating the generation of leukemia-reactive cytotoxic T lymphocyte lines for treatment of patients with relapsed leukaemia after allogeneic stem cell transplantation. Haematologica 92:72–80CrossRefPubMedGoogle Scholar
  8. 8.
    Gattinoni L, Klebanoff CA, Palmer DC et al (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8 T cells. J Clin Invest 115:1616–1626CrossRefPubMedGoogle Scholar
  9. 9.
    Smyth MJ, Dunn GP, Schreiber RD (2006) Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90:1–50CrossRefPubMedGoogle Scholar
  10. 10.
    Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6:383–393CrossRefPubMedGoogle Scholar
  11. 11.
    Girardi M, Oppenheim DE, Steele CR et al (2001) Regulation of cutaneous malignancy by γδ T cells. Science 294:605–609CrossRefPubMedGoogle Scholar
  12. 12.
    Belmant C, Decise D, Fournie JJ (2006) Phosphoantigens and aminobisphosphonates: new leads targeting γδ T lymphocytes for cancer immunotherapy. Drug Discov Today Ther Strateg 3:17–23CrossRefGoogle Scholar
  13. 13.
    Liu Z, Guo BL, Gehrs BC, Nan L, Lopez RD (2005) Ex vivo expanded human Vγ9Vδ2+ γδ T cells mediate innate antitumor activity against human prostate cancer cells in vitro. J Urol 173:1552–1556CrossRefPubMedGoogle Scholar
  14. 14.
    Kabelitz D, Wesch D, Pitters E, Zoller M (2004) Characterization of tumor reactivity of human Vγ9Vδ2 γδT cells in vitro and in SCID mice in vivo. J Immunol 173:6767–6776PubMedGoogle Scholar
  15. 15.
    Tanaka Y, Morita CT, Tanaka Y, Nieves E, Brenner MB, Bloom BR (1995) Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature 375:155–158CrossRefPubMedGoogle Scholar
  16. 16.
    Harwood HJ Jr, Alvarez IM, Noyes WD, Stacpoole PW (1991) In vivo regulation of human leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase: increased enzyme protein concentration and catalytic efficiency in human leukemia and lymphoma. J Lipid Res 32:1237–1252PubMedGoogle Scholar
  17. 17.
    Gober HJ, Kistowska M, Angman L, Jenö P, Mori L, De Libero G (2003) Human T cell receptor γδ cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197:163–168CrossRefPubMedGoogle Scholar
  18. 18.
    Kunzmann V, Bauer E, Wilhelm M (1999) γδ T-cell stimulation by pamidronate. N Engl J Med 340:737–738CrossRefPubMedGoogle Scholar
  19. 19.
    Roelofs AJ, Jauhiainen M, Monkkonen H, Rogers MJ, Monkkonen J, Thompson K (2009) Peripheral blood monocytes are responsible for γδ T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol 144:245–250CrossRefPubMedGoogle Scholar
  20. 20.
    Li J, Herold MJ, Kimmel B, Müller I, Rincon-Orozco B, Kunzmann V, Herrmann T (2009) Reduced expression of the mevalonate pathway enzyme farnesyl pyrophosphate synthase unveils recognition of tumor cells by Vγ9Vδ2 T cells. J Immunol 182:8118–8124CrossRefPubMedGoogle Scholar
  21. 21.
    Das H, Groh V, Kuijl C, Sugita M, Morita CT, Spies T, Bukowski JF (2001) MICA engagement by human Vγ2Vδ2 T cells enhances their antigen-dependent effector function. Immunity 15:83–93CrossRefPubMedGoogle Scholar
  22. 22.
    Girlanda S, Fortis C, Belloni D et al (2005) MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells co-stimulates pamidronate-activated γδ lymphocytes. Cancer Res 65:7502–7508CrossRefPubMedGoogle Scholar
  23. 23.
    Lança T, Correia DV, Moita CF et al (2010) The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to γδ T-cell cytotoxicity. Blood 115:2407–2411CrossRefPubMedGoogle Scholar
  24. 24.
    Gomes AQ, Correia DV, Grosso AR et al (2010) Identification of a panel of ten cell surface protein antigens associated with immunotargeting of leukemias and lymphomas by peripheral blood γδ T cells. Haematologica (in press)Google Scholar
  25. 25.
    Dalton JE, Howell G, Pearson J, Scott P, Carding SR (2004) Fas-Fas ligand interactions are essential for the binding to and killing of activated macrophages by gamma delta T cells. J Immunol 173:3660–3667PubMedGoogle Scholar
  26. 26.
    Dieli F, Troye-Blomberg M, Ivanyi J et al (2001) Granulysin-dependent killing of intracellular and extracellular Mycobacterium tuberculosis by Vgamma9/Vdelta2 T lymphocytes. J Infect Dis 184:1082–1085CrossRefPubMedGoogle Scholar
  27. 27.
    Vermijlen D, Ellis P, Langford C et al (2007) Distinct cytokine-driven responses of activated blood γδ T cells: insights into unconventional T cell pleiotropy. J Immunol 178:4304–4314PubMedGoogle Scholar
  28. 28.
    Carding SR, Egan PJ (2002) γδ T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2:336–345CrossRefPubMedGoogle Scholar
  29. 29.
    Ismaili J, Olislagers V, Poupot R, Fournie JJ, Goldman M (2002) Human γδ T cells induce dendritic cell maturation. Clin Immunol 103:296–302CrossRefPubMedGoogle Scholar
  30. 30.
    Sicard H, Ingoure S, Luciani B et al (2005) In vivo immunomanipulation of Vγ9Vδ2 T cells with a synthetic phosphoantigen in a preclinical nonhuman primate model. J Immunol 175:5471–5480PubMedGoogle Scholar
  31. 31.
    Casetti R, Perretta G, Taglioni A et al (2005) Drug-induced expansion and differentiation of Vγ9Vδ2 T cells in vivo: the role of exogenous IL-2. J Immunol 175:1593–1598PubMedGoogle Scholar
  32. 32.
    Kobayashi H, Tanaka Y, Yagi J et al (2007) Safety profile and anti-tumour effects of adoptive immunotherapy using γδ T cells against advanced renal cell carcinoma: a pilot study. Cancer Immunol Immunother 56:469–476CrossRefPubMedGoogle Scholar
  33. 33.
    Bennouna J, Bompas E, Neidhardt EM et al (2008) Phase-I study of Innacell γδ, an autologous cell-therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother 57:1599–1609CrossRefPubMedGoogle Scholar
  34. 34.
    Kobayashi H, Tanaka Y, Shimmura H, Minato N, Tanabe K (2010) Complete remission of lung metastasis following adoptive immunotherapy using activated autologous γδ T-cells in a patient with renal cell carcinoma. Anticancer Res 30:575–579PubMedGoogle Scholar
  35. 35.
    Abe Y, Muto M, Nieda M et al (2009) Clinical and immunological evaluation of zoledronate-activated Vgamma9 gamma delta T-cell-based immunotherapy for patients with multiple myeloma. Exp Hematol 37:956–968CrossRefPubMedGoogle Scholar
  36. 36.
    Nakajima J, Murakawa T, Fukami T et al (2010) A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous γδ T cells. Eur J Cardiothorac Surg 37:1191–1197CrossRefPubMedGoogle Scholar
  37. 37.
    Wilhelm M, Kunzmann V, Eckstein S, Reimer P, Weissinger F, Ruediger T, Tony HP (2003) γδ T cells for immune therapy of patients with lymphoid malignancies. Blood 102:200–206CrossRefPubMedGoogle Scholar
  38. 38.
    Dieli F, Vermijlen D, Fulfaro F et al (2007) Targeting human γδ T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 67:7450–7457CrossRefPubMedGoogle Scholar
  39. 39.
    Meraviglia S, Eberl M, Vermijlen D et al (2010) In vivo manipulation of Vγ9Vδ2 T cells with zoledronate and low dose interleukin-2 for immunotherapy of advanced breast cancer patients. Clin Exp Immunol (in press)Google Scholar
  40. 40.
    Davodeau F, Peyrat MA, Hallet MM et al (1993) Close correlation between Daudi and mycobacterial antigen recognition by human gamma delta T cells and expression of V9JPC1 gamma/V2DJC delta-encoded T cell receptors. J Immunol 151:1214–1223PubMedGoogle Scholar
  41. 41.
    Selin LK, Stewart S, Shen C, Mao HQ, Wilkins JA (1992) Reactivity of gamma delta T cells induced by the tumor cell line RPMI 8226: functional heterogeneity of clonal population and role of GroEL heat shock proteins. Scand J Immunol 36:107–117CrossRefPubMedGoogle Scholar
  42. 42.
    Tokuyama H, Hagi T, Mattarollo SR et al (2008) Vγ9Vδ2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs—rituximab and trastuzumab. Int J Cancer 112:2526–2534CrossRefGoogle Scholar
  43. 43.
    Burjanadze M, Condomines M, Reme T et al (2007) In vitro expansion of gamma delta T cells with anti-myeloma cell activity by phosphostim and IL-2 in patients with multiple myeloma. Br J Haematol 139:206–216CrossRefPubMedGoogle Scholar
  44. 44.
    Espinosa E, Belmant C, Pont F et al (2001) Chemical synthesis and biological activity of bromohydrin pyrophosphate, a potent stimulator of human gamma delta T cells. J Biol Chem 276:18337–18344CrossRefPubMedGoogle Scholar
  45. 45.
    Gazitt Y, Akay C (2004) Mobilization of myeloma cells involves SDF-1/CXCR4 signaling and downregulation of VLA-4. Stem Cells 22:65–73CrossRefPubMedGoogle Scholar
  46. 46.
    Alsayed Y, Ngo H, Runnels J et al (2006) Mechanisms of regulation of CXCR4/SDF-1 (CXCL12) dependent migration and homing in multiple myeloma. Blood 109:2708–2717Google Scholar
  47. 47.
    D’Asaro M, La Mendola C, Di Liberto D et al (2010) Vgamma9Vdelta2 T lymphocytes efficiently recognize and kill zoledronate-sensitized, imatinib-sensitive, and imatinib-resistant chronic myelogenous leukemia cells. J Immunol 184:3260–3268CrossRefPubMedGoogle Scholar
  48. 48.
    Goldman JM, Melo JV (2003) Chronic myeloid leukemia advances in biology and new approaches to treatment. N Engl J Med 349:1451–1464CrossRefPubMedGoogle Scholar
  49. 49.
    Sawyers CL, Hochhaus A, Feldman E et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539CrossRefPubMedGoogle Scholar
  50. 50.
    Kantarjian H, Sawyers C, Hochhaus A et al (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652CrossRefPubMedGoogle Scholar
  51. 51.
    Ottmann OG, Druker BJ, Sawyers CL et al (2002) A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100:1965–1971CrossRefPubMedGoogle Scholar
  52. 52.
    Segawa H, Kimura S, Kuroda J et al (2005) Zoledronate synergises with imatinib mesylate to inhibit Ph primary leukaemic cell growth. Br J Haematol 130:558–560CrossRefPubMedGoogle Scholar
  53. 53.
    Kuroda J, Kimura S, Segawa H et al (2003) The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph + leukemia activity of imatinib mesylate. Blood 102:2229–2235CrossRefPubMedGoogle Scholar
  54. 54.
    Chuah C, Barnes DJ, Kwok M, Corbin A, Deininger MW, Druker BJ, Melo JV (2005) Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells. Leukemia 19:1896–1904CrossRefPubMedGoogle Scholar
  55. 55.
    Mattarollo SR, Kenna T, Nieda M, Nicol AJ (2007) Chemotherapy and zoledronate sensitize solid tumour cells to Vγ9Vδ2 T cell cytotoxicity. Cancer Immunol Immunother 56:1285–1297CrossRefPubMedGoogle Scholar
  56. 56.
    Stagno F, Stella S, Berretta S et al (2008) Sequential mutations causing resistance to both imatinib mesylate and dasatinib in a chronic myeloid leukaemia patient progressing to lymphoid blast crisis. Leuk Res 32:673–674CrossRefPubMedGoogle Scholar
  57. 57.
    Kato Y, Tanaka Y, Miyagawa F, Yamashita S, Minato N (2001) Targeting of tumor cells for human γδ T cells by nonpeptide antigens. J Immunol 167:5092–5098PubMedGoogle Scholar
  58. 58.
    Santini D, Vincenzi B, Avvisati G et al (2002) Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8:1080–1084PubMedGoogle Scholar
  59. 59.
    Gertner-Dardenne J, Bonnafous C, Bezombes C et al (2009) Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies. Blood 113:4875–4884CrossRefPubMedGoogle Scholar
  60. 60.
    Carter PJ (2006) Potent antibody therapeutics by design. Nat Rev Immunol 6:343–357CrossRefPubMedGoogle Scholar
  61. 61.
    Cartron G, Watier H, Golay J, Solal-Celigny P (2004) From the bench to the bedside: ways to improve rituximab efficacy. Blood 104:2635–2642CrossRefPubMedGoogle Scholar
  62. 62.
    Coiffier B (2007) Rituximab therapy in malignant lymphoma. Oncogene 26:3603–3613CrossRefPubMedGoogle Scholar
  63. 63.
    June CH, Blazar BR, Riley JL (2009) Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol 9:704–716CrossRefPubMedGoogle Scholar
  64. 64.
    Green AE, Lissina A, Hutchinson SL et al (2004) Recognition of nonpeptide antigens by human Vγ9Vδ2 T cells requires contact with cells of human origin. Clin Exp Immunol 136:472–482CrossRefPubMedGoogle Scholar
  65. 65.
    Tough DF, Sprent J (1998) Lifespan of γδ T cells. J Exp Med 187:357–365CrossRefPubMedGoogle Scholar
  66. 66.
    Kunzmann V, Kimmel B, Herrmann T, Einsele H, Wilhelm M (2009) Inhibition of phosphoantigen-mediated γδ T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells. Immunology 126:256–267CrossRefPubMedGoogle Scholar
  67. 67.
    Gattinoni L, Finkelstein SE, Klebanoff CA et al (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor specific CD8 T cells. J Exp Med 202:907–912CrossRefPubMedGoogle Scholar
  68. 68.
    Robbins PF, Dudley ME, Wunderlich J et al (2004) Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol 173:7125–7130PubMedGoogle Scholar
  69. 69.
    Huang J, Khong HT, Dudley ME et al (2005) Survival, persistence, and progressive differentiation of adoptively transferred tumour-reactive T cells associated with tumour regression. J Immunother 28:258–267CrossRefPubMedGoogle Scholar
  70. 70.
    Zhou J, Shen X, Huang J, Hodes RJ, Rosenberg SA, Robbins PF (2005) Telomere length of transferred lymphocytes correlates with in vivo persistence and tumour regression in melanoma patients receiving cell transfer therapy. J Immunol 175:7046–7052PubMedGoogle Scholar
  71. 71.
    Giachino C, Granziero L, Modena V et al (1994) Clonal expansions of VγVδ1 and Vδ2 cells increase with age and limit the repertoire of human γδ T cells. Eur J Immunol 24:1914–1918CrossRefPubMedGoogle Scholar
  72. 72.
    Caccamo N, Dieli F, Wesch D, Jomaa H, Eberl M (2006) Sex-specific phenotypical and functional differences in peripheral human Vγ9Vδ2 T cells. J Leukoc Biol 79:663–666CrossRefPubMedGoogle Scholar
  73. 73.
    Li B, Rossman MD, Imir T, Oner-Eyuboglu AF, Lee CW, Biancaniello R, Carding SR (1996) Disease-specific changes in γδ T cell repertoire and function in patients with pulmonary tuberculosis. J Immunol 157:4222–4229PubMedGoogle Scholar
  74. 74.
    Hara T, Ohashi S, Yamashita Y et al (1996) Human Vδ2 γδ T-cell tolerance to foreign antigens of Toxoplasma gondii. Proc Natl Acad Sci USA 93:5136–5140CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Serena Meraviglia
    • 1
  • Carmela La Mendola
    • 1
  • Valentina Orlando
    • 1
  • Francesco Scarpa
    • 1
  • Giuseppe Cicero
    • 2
  • Francesco Dieli
    • 1
  1. 1.Dipartimento di Biopatologia e Biotecnologie Mediche e ForensiUniversità di PalermoPalermoItaly
  2. 2.Dipartimento di Discipline Chirurgiche ed OncologicheUniversità di PalermoPalermoItaly

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