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Cytotechnology

, Volume 68, Issue 4, pp 735–748 | Cite as

A comparison between cytokine- and bead-stimulated polyclonal T cells: the superiority of each and their possible complementary role

  • Weng-Chee Chan
  • Yeh-Ching LinnEmail author
Original Research

Abstract

Cytokine-induced killer (CIK) cells and T cells expanded by co-stimulation with beads presenting anti-CD3 and -CD28 antibodies are both polyclonal T cells under intensive laboratory and clinical studies, but there has not been any direct comparison between both. We compared the expansion, memory T cell subsets and cytotoxicity for T cells expanded in parallel by the two methods. Bead-stimulated T cells showed superior expansion as compared to CIK cells on D14 of culture. Bead-stimulated T cells consisted of a significantly higher CD4+ subset and significantly lower CD8+ subset as compared to CIK cells, as well as a higher proportion of less terminally differentiated T cells and a higher proportion of homing molecules. On the other hand, CIK cells exhibited significantly superior cytotoxicity against two myelomonocytic leukemia cell lines (THP-1 and U937) and two RCC cell lines (786.0 and CaKi-2). The cytotoxicity on D14 against THP-1 was 58.1 % for CIK cells and 8.3 % for bead-stimulated T cells at E:T of 10:1 (p < 0.01). Cytotoxicity correlated positively with the proportion of the CD8 subset in the culture and was independent of NKG2D recognition of susceptible targets. Polyclonal T cells expanded by different methods exhibit different characteristics which may define the specific role of each in different clinical scenario. We postulate that the more potent CIK cells may offer short term benefit while bead-stimulated T cells may offer a more sustained immune response.

Keywords

Cytokine-induce killer cells CD3/CD28 beads co-stimulated T cells Cytotoxicity Memory T cell subsets 

Notes

Acknowledgments

The authors would like to thank their laboratory colleagues in Singapore General Hospital and National Cancer Center for their kind assistance in one way or other. This work was supported by funding from SingHealth Foundation PTC02/2007/005.

Conflict of interest

The authors declare no conflict of interest.

References

  1. Borrello IM, Vij R, Vescio RA, Martin TG, Siegel D, Berenson JR, Janmohamed F, Bonyhadi M, Berenson RJ, Frohlich MW (2004) A phase I/II study of Xcellerated T cells after autologous peripheral blood stem cell transplantation in patients with multiple myeloma. J Clin Oncol 22:2540 (2004 ASCO Annual Meeting Proceedings, July 15 Supplement) Google Scholar
  2. Brentjens RJ, Rivière 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 118:4817–4828CrossRefGoogle Scholar
  3. Durrieu L, Gregoire-Gauthier J, Dieng MM, Fontaine F, le Deist F, Haddad E (2012) Human interferon-alpha increases the cytotoxic effect of CD56(+) cord blood-derived cytokine-induced killer cells on human B-acute lymphoblastic leukemia cell lines. Cytotherapy 14:1245–1257CrossRefGoogle Scholar
  4. Gammaitoni L, Giraudo L, Leuci V, Todorovic M, Mesiano G, Picciotto F, Pisacane A, Zaccagna A, Volpe MG, Gallo S, Caravelli D, Giacone E, Venesio T, Balsamo A, Pignochino Y, Grignani G, Carnevale-Schianca F, Aglietta M, Sangiolo D (2013) Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features. Clin Cancer Res 19:4347–4358CrossRefGoogle Scholar
  5. Garlie NK, LeFever AV, Siebenlist RE, Levine BL, June CH, Lum LG (1999) T cells coactivated with immobilized anti-CD3 and anti-CD28 as potential immunotherapy for cancer. J Immunother 22:336–345CrossRefGoogle Scholar
  6. 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 Investig 115:1616–1626Google Scholar
  7. Hontscha C, Borck Y, Zhou H, Messmer D, Schmidt-Wolf IGH (2011) Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 137:305–310CrossRefGoogle Scholar
  8. Hoyle C, Bangs CD, Chang P, Kamel O, Mehta B, Negrin RS (1998) Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice. Blood 92:3318–3327Google Scholar
  9. Introna M, Franceschetti M, Ciocca A, Borleri G, Conti E, Golay J, Rambaldi A (2006) Rapid and massive expansion of cord blood-derived cytokine-induced killer cells: an innovative proposal for the treatment of leukemia relapse after cord blood transplantation. Bone Marrow Transpl 38:621–627CrossRefGoogle Scholar
  10. Introna M, Borleri G, Conti E, Franceschetti M, Barbui AM, Broady R, Dander E, Gaipa G, D’Amico G, Biagi E, Parma M, Pogliani EM, Spinelli O, Baronciani D, Grassi A, Golay J, Barbui T, Biondi A, Rambaldi A (2007) Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica 92:952–959CrossRefGoogle Scholar
  11. Jiang H, Liu KY, Tong CR, Jiang B, Lu DP (2005) The efficacy of chemotherapy in combination with auto-cytokine-induced killer cells in acute leukemia. Zhonghua Nei Ke Za Zhi 44:198–201Google Scholar
  12. 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 3:95ra73CrossRefGoogle Scholar
  13. Karimi M, Cao TM, Baker JA, Verneris MR, Soares L, Negrin RS (2005) Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated CD8+ T cells and NK cells. J Immunol 175:7819–7828CrossRefGoogle Scholar
  14. Kuçi S, Rettinger E, Voss B, Weber G, Stais M, Kreyenberg H, Willasch A, Kuçi Z, Koscielniak E, Klöss S, von Laer D, Klingebiel T, Bader P (2010) Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: implications for adoptive immunotherapy after allogeneic stem cell transplantation. Haematologica 95:1579–1586CrossRefGoogle Scholar
  15. Laport GG, Levine BL, Stadtmauer EA, Schuster SJ, Luger SM, Grupp S, Bunin N, Strobl FJ, Cotte J, Zheng Z, Gregson B, Rivers P, Vonderheide RH, Liebowitz DN, Porter DL, June CH (2003) Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+ -selected hematopoietic cell transplantation. Blood 102:2004–2013CrossRefGoogle Scholar
  16. Laport GG, Sheehan K, Baker J, Armstrong R, Wong RM, Lowsky R, Johnston LJ, Shizuru JA, Miklos D, Arai S, Benjamin JE, Weng WK, Negrin RS (2011) Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl 17:1679–1687CrossRefGoogle Scholar
  17. Leemhuis T, Wells S, Scheffold C, Edinger M, Negrin RS (2005) A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transpl 11:181–187CrossRefGoogle Scholar
  18. Lefterova P, Schakowski F, Buttgereit P, Scheffold C, Huhn D, Schmidt-Wolf IG (2000) Expansion of CD3+CD56+ cytotoxic cells from patients with chronic lymphocytic leukemia: in vitro efficacy. Haematologica 85:1108–1109Google Scholar
  19. Levine BL, Bernstein WB, Connors M, Craighead N, Lindsten T, Thompson CB, June CH (1997) Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the absence of exogenous feeder cells. J Immunol 159:5921–5930Google Scholar
  20. Levine BL, Cotte J, Small CC, Carroll RG, Riley JL, Bernstein WB, Van Epps DE, Hardwick RA, June CH (1998) Large-scale production of CD4+ T cells from HIV-1-infected donors after CD3/CD28 costimulation. J Hematother 7:437–448CrossRefGoogle Scholar
  21. Levine BL, Bernstein WB, Aronson NE, Schlienger K, Cotte J, Perfetto S, Humphries MJ, Ratto-Kim S, Birx DL, Steffens C, Landay A, Carroll RG, June CH (2002) Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med 8:47–53CrossRefGoogle Scholar
  22. Li Y, Kurlander RJ (2010) Comparison of anti-CD3 and anti-CD28-coated beads with soluble anti-CD3 for expanding human T cells: differing impact on CD8 T cell phenotype and responsiveness to restimulation. J Transl Med 8:104CrossRefGoogle Scholar
  23. Li JJ, Gu MF, Pan K, Liu LZ, Zhang H, Shen WX, Xia JC (2012a) Autologous cytokine-induced killer cell transfusion in combination with gemcitabine plus cisplatin regimen chemotherapy for metastatic nasopharyngeal carcinoma. J Immunother 35:189–195CrossRefGoogle Scholar
  24. Li R, Wang C, Liu L, Du C, Cao S, Yu J, Wang SE, Hao X, Ren X, Li H (2012b) Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study. Cancer Immunol Immunother 61:2125–2133CrossRefGoogle Scholar
  25. Linn YC, Lau LC, Hui KM (2002) Generation of cytokine-induced killer cells from leukaemic samples with in vitro cytotoxicity against autologous and allogeneic leukaemic blasts. Br J Haematol 116:78–86CrossRefGoogle Scholar
  26. Linn YC, Lau SKJ, Liu BH, Ng LH, Yong HX, Hui KM (2009) Characterization of the recognition and functional heterogeneity exhibited by cytokine-induced killer cell subsets against acute myeloid leukaemia target cell. Immunology 126:423–435CrossRefGoogle Scholar
  27. Linn YC, Niam M, Chu S, Choong A, Yong HX, Heng KK, Hwang W, Loh Y, Goh YT, Suck G, Chan M, Koh M (2012a) The anti-tumour activity of allogeneic cytokine-induced killer cells in patients who relapse after allogeneic transplant for haematological malignancies. Bone Marrow Transpl 47:957–966CrossRefGoogle Scholar
  28. Linn YC, Yong HX, Niam M, Lim TJ, Chu S, Choong A, Chuah C, Goh YT, Hwang W, Loh Y, Ng HJ, Suck G, Chan M, Koh M (2012b) A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission. Cytotherapy 14:851–859CrossRefGoogle Scholar
  29. Liu L, Zhang W, Qi X, Li H, Yu J, Wei S, Hao X, Ren X (2012) Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res 18:1751–1759CrossRefGoogle Scholar
  30. Lu PH, Negrin RS (1994) A novel population of expanded human CD3+ CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol 153:1687–1696Google Scholar
  31. Lum LG, LeFever AV, Treisman JS, Garlie NK, Hanson JP Jr (2001) Immune Modulation in Cancer Patients After Adoptive Transfer of Anti-CD3/Anti-CD28-Costimulated T Cells-Phase I Clinical Trial. J Immunother 24:408–419CrossRefGoogle Scholar
  32. Mesiano G, Todorovic M, Gammaitoni L, Leuci V, Giraudo Diego L, Carnevale-Schianca F, Fagioli F, Piacibello W, Aglietta M, Sangiolo D (2012) Cytokine-induced killer (CIK) cells as feasible and effective adoptive immunotherapy for the treatment of solid tumors. Expert Opin Biol Ther 12:673–684CrossRefGoogle Scholar
  33. Niam M, Linn YC, Fook Chong S, Lim TJ, Chu S, Choong A, Yong HX, Suck G, Chan M, Koh M (2011) Clinical scale expansion of cytokine-induced killer cells is feasible from healthy donors and patients with acute and chronic myeloid leukemia at various stages of therapy. Exp Hematol 39(897.e1):903.e1Google Scholar
  34. Pan K, Li YQ, Wang W, Xu L, Zhang YJ, Zheng HX, Zhao JJ, Qiu HJ, Weng DS, Li JJ, Wang QJ, Huang LX, He J, Chen SP, Ke ML, Wu PH, Chen MS, Li SP, Xia JC, Zeng YX (2013) The efficacy of cytokine-induced killer cell infusion as an adjuvant therapy for postoperative hepatocellular carcinoma patients. Ann Surg Oncol 20:4305–4311CrossRefGoogle Scholar
  35. Pan K, Wang QJ, Liu Q, Zheng HX, Li YQ, Weng DS, Li JJ, Huang LX, He J, Chen SP, Ke ML, Zeng YX, Xia JC (2014) The phenotype of ex vivo generated cytokine-induced killer cells is associated with overall survival in patients with cancer. Tumour Biol 35:701–707CrossRefGoogle Scholar
  36. Porter DL, Levine BL, Bunin N, Stadtmauer EA, Luger SM, Goldstein S, Loren A, Phillips J, Nasta S, Perl A, Schuster S, Tsai D, Sohal A, Veloso E, Emerson S, June CH (2006) A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood 107:1325–1331CrossRefGoogle Scholar
  37. Rapoport AP, Levine BL, Badros A, Meisenberg B, Ruehle K, Nandi A, Rollins S, Natt S, Ratterree B, Westphal S, Mann D, June CH (2004) Molecular remission of CML after autotransplantation followed by adoptive transfer of costimulated autologous T cells. Bone Marrow Transpl 33:53–60CrossRefGoogle Scholar
  38. Rapoport AP, Stadtmauer EA, Aqui N, Badros A, Cotte J, Chrisley L, Veloso E, Zheng Z, Westphal S, Mair R, Chi N, Ratterree B, Pochran MF, Natt S, Hinkle J, Sickles C, Sohal A, Ruehle K, Lynch C, Zhang L, Porter DL, Luger S, Guo C, Fang HB, Blackwelder W, Hankey K, Mann D, Edelman R, Frasch C, Levine BL, Cross A, June CH (2005) Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 11:1230–1237CrossRefGoogle Scholar
  39. Rapoport AP, Stadtmauer EA, Aqui N, Vogl D, Chew A, Fang HB, Janofsky S, Yager K, Veloso E, Zheng Z, Milliron T, Westphal S, Cotte J, Huynh H, Cannon A, Yanovich S, Akpek G, Tan M, Virts K, Ruehle K, Harris C, Philip S, Vonderheide RH, Levine BL, June CH (2009) Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells. Clin Cancer Res 15:4499–4507CrossRefGoogle Scholar
  40. Rettinger E, Kuçi S, Naumann I, Becker P, Kreyenberg H, Anzaghe M, Willasch A, Koehl U, Bug G, Ruthardt M, Klingebiel T, Fulda S, Bader P (2012) The cytotoxic potential of interleukin-15-stimulated cytokine-induced killer cells against leukemia cells. Cytotherapy 14:91–103CrossRefGoogle Scholar
  41. Rettinger E, Bonig H, Wehner S, Lucchini G, Willasch A, Jarisch A, Soerensen J, Esser R, Rossig C, Klingebiel T, Bader P (2013) Feasibility of IL-15-activated cytokine-induced killer cell infusions after haploidentical stem cell transplantation. Bone Marrow Transpl 48:1141–1143 Google Scholar
  42. Sangiolo D, Martinuzzi E, Todorovic M, Vitaggio K, Vallario A, Jordaney N, Carnevale-Schianca F, Capaldi A, Geuna M, Casorzo L, Nash RA, Aglietta M, Cignetti A (2008) Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers. Int Immunol 20:841–848CrossRefGoogle Scholar
  43. Sangiolo D, Mesiano G, Gammaitoni L, Leuci V, Todorovic M, Giraudo L, Cammarata C, Dell’Aglio C, D’Ambrosio L, Pisacane A, Sarotto I, Miano S, Ferrero I, Carnevale-Schianca F, Pignochino Y, Sassi F, Bertotti A, Piacibello W, Fagioli F, Aglietta M, Grignani G (2014) Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas. Cancer Res 74:119–129CrossRefGoogle Scholar
  44. Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL (1991) Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med 174:139–149CrossRefGoogle Scholar
  45. Shi L, Zhou Q, Wu J, Ji M, Li G, Jiang J, Wu C (2012) Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol Immunother 61:2251–2259CrossRefGoogle Scholar
  46. Thanendrarajan S, Kim Y, Schmidt-Wolf I (2012) New adoptive immunotherapy strategies for solid tumours with CIK cells. Expert Opin Biol Ther 12:565–572CrossRefGoogle Scholar
  47. Thompson JA, Figlin RA, Sifri-Steele C, Berenson RJ, Frohlich MW (2003) A phase I trial of CD3/CD28-activated T cells (Xcellerated T cells) and interleukin-2 in patients with metastatic renal cell carcinoma. Clin Cancer Res 9:3562–3570Google Scholar
  48. Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS (2004) Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 103:3065–3072CrossRefGoogle Scholar
  49. Wierda WG, Kipps TJ, Castro J, Keating MJ, Bole J, Anderson B, Meyer J, Anderson K, Berenson R J, Frohlich MW (2004) A Phase I/II trial of CD3/CD28 activated T cells in patients with chronic lymphocytic leukemia (CLL). J Clin Oncol 22:2566 (2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition), July 15 Supplement) Google Scholar
  50. Zou Y, Li F, Hou W, Sampath P, Zhang Y, Thorne SH (2014) Manipulating the expression of chemokine receptors enhances delivery and activity of cytokine-induced killer cells. Br J Cancer 110:1992–1999CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.School of Biological SciencesNanyang Technological UniversitySingaporeSingapore
  2. 2.Department of HaematologySingapore General HospitalSingaporeSingapore

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