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Chronic Myelocytic Leukemia (CML) Patient-Derived Dendritic Cells Transfected with Autologous Total RNA Induces CML-Specific Cytotoxicity

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Indian Journal of Hematology and Blood Transfusion Aims and scope Submit manuscript

Abstract

The oncogenic bcr/abl1 fusion gene is a chronic myelogenous leukemia (CML)-specific antigen which is absent in normal tissues. This makes bcr/abl1 a perfect target for developing CML vaccines that elicit specific immune responses against minimal residual disease while sparing normal tissue. The aim of this study was to use different methods to induce dendritic cells (DCs) derived from patients with CML (CML-DCs) and analyze them for CML-specific tumor cytotoxicity for immune therapy. Bone marrow-derived mononuclear cells from ten CML patients were studied to induce CML-DC differentiation in the presence of recombinant human interleukin-4, rh-granulocyte-macrophage-colony stimulating factor, and tumor necrosis factor-alpha with either a total RNA-lipofectamine complex, total RNA or CML tumor lysate (freeze–thawed). CML-DC maturation, confirmed by expression of CD1α, CD40, CD80, CD83, CD86 and by real-time polymerase chain reaction, validated the CML-origin of these DC cells. CML-DCs stimulated cytotoxic T-cell (CTL) apoptosis, high levels of IL-12 secretion, and had significant inhibitory effect on K562 tumorigenicity in nude mice. CML-DCs pulsed with total RNA by lipofectamine transfection produced the strongest effect in tumor-specific CTL functions. These results indicate that CML-DCs transfected with total RNA by lipofectamine induce the strongest CTL cytotoxicity and have the greatest potential for CML immune therapy. This study holds promise for a DC-based strategy for inducing anti-leukemia responses and establishes a foundation for developing RNA vaccination against CML.

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References

  1. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355(23):2408–2417

    Article  CAS  PubMed  Google Scholar 

  2. Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B et al (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354(24):2542–2551

    Article  PubMed  Google Scholar 

  3. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ et al (2007) Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109(6):2303–2309

    Article  CAS  PubMed  Google Scholar 

  4. Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112(12):4371–4383

    Article  CAS  PubMed  Google Scholar 

  5. Biernacki MA, Marina O, Zhang W, Liu F, Bruns I, Cai A et al (2010) Antigen targets of remission-inducing immune therapy are expressed on CML progenitor cells. Cancer Res 70(3):906–915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Christian MS, Carsten R, Adrian F, Ochsenbein AF (2012) Dendritic cell-based immunotherapy for myeloid leukemias. Semin Cancer Biol 22(4):298–306

    Article  Google Scholar 

  7. Sylvia B, Elena P, Anna S, Marina R, Claudia B, Elke D et al (2011) Genetically modified donor leukocyte transfusion and graft-versus-leukemia effect after allogeneic stem cell transplantation. Hum Gene Ther 22:829–841

    Article  Google Scholar 

  8. Mohty M, Isnardon D, Vey N, Briere F, Blaise D, Olive D et al (2002) Low blood dendritic cells in chronic myeloid leukaemia patients correlates with loss of CD34+/CD38 primitive haematopoietic progenitors. Br J Haematol 119(1):115–118

    Article  PubMed  Google Scholar 

  9. Boissel N, Rousselot P, Raffoux E, Cayuela JM, Maarek O, Charron D et al (2004) Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate. Leukemia 18(10):1656–1661

    Article  CAS  PubMed  Google Scholar 

  10. Zha X, Yan X, Shen Q, Zhang Y, Wu X, Chen S et al (2012) Alternative expression of TCRζ related genes in patients with chronic myeloid leukemia. J Hematol Oncol 5:74–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Qin YN, Tian H, Wang G, Lin C, Li Y (2013) A BCR/ABL-hIL-2 DNA vaccine enhances the immune responses in BALB/c mice. BioMed Res Int 2013:136492

    PubMed  PubMed Central  Google Scholar 

  12. Sloma I, Jiang X, Eaves AC, Eaves CJ (2010) Insights into the stem cells of chronic myeloid leukemia. Leukemia 24(11):1823–1833

    Article  CAS  PubMed  Google Scholar 

  13. Westermann J, Kopp J, van Lessen A, Hecker AC, Baskaynak G, le Coutre P et al (2007) Vaccination with autologous non-irradiated dendritic cells in patients with bcr/abl+ chronic myeloid leukaemia. Br J Haematol 137(4):297–306

    Article  CAS  PubMed  Google Scholar 

  14. Eisendle K, Lang A, Eibl B, Nachbaur D, Glassl H, Fiegl M, Thaler J, Gastl G (2003) Phenotypic and functional deficiencies of leukaemic dendritic cells from patients with chronic myeloid leukaemia. Br J Haematol 120:63–73

    Article  PubMed  Google Scholar 

  15. Mumprecht S, Claus C, Schurch C, Pavelic V, Matter MS, Ochsenbein AF (2009) Defective homing and impaired induction of cytotoxic T cells by BCR/ABL-expressing dendritic cells. Blood 113(19):4681–4689

    Article  CAS  PubMed  Google Scholar 

  16. Held SA, Heine A, Mayer KT, Kapelle M, Wolf DG, Brossart P (2013) Advances in immunotherapy of chronic myeloid leukemia CML. Curr Cancer Drug Targets 13(7):768–774

    Article  CAS  PubMed  Google Scholar 

  17. Schürch CM, Riether C, Ochsenbein AF (2013) Dendritic cell-based immunotherapy for myeloid leukemias. Front Immunol 4:496

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ma Y, Shurin GV, Gutkin DW, Shurin MR (2012) Tumor associated regulatory dendritic cells. Semin Cancer Biol 22(4):298–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ana B, Ursula H, Martha W, Donna N, Mei S, Christine M et al (2012) Detecting T-cell reactivity to whole cell vaccines proof of concept analysis of T-cell response to K562 cell antigens in CML patients. OncoImmunology 1(7):1095–1103

    Article  Google Scholar 

  20. Westers TM, van den Ancker W, Bontkes HJ, Janssen JJ, van de Loosdrecht AA, Ossenkoppele GJ (2011) Chronic myeloid leukemia lysate-loaded dendritic cells induce T-cell responses towards leukemia progenitor cells. Immunotherapy 3(4):569–576

    Article  CAS  PubMed  Google Scholar 

  21. Pfaar O, Cazan D, Klimek L, Larenas-Linnemann D, Calderon MA (2012) Adjuvants for immunotherapy. Curr Opin Allergy Clin Immunol 12(6):648–657

    Article  CAS  PubMed  Google Scholar 

  22. Li YQ, Lin C, Christian AS (2012) New insights into antigen specific immunotherapy for chronic myeloid leukemia. Cancer Cell Int 12:52–60

    Article  PubMed  PubMed Central  Google Scholar 

  23. Iancu EM, Baumgaertner P, Wieckowski S, Speiser DE, Rufer N (2011) Profile of a serial killer: cellular and molecular approaches to study individual cytotoxic T-cells following therapeutic vaccination. J Biomed Biotechnol. 2011:452606

    Article  PubMed  Google Scholar 

  24. Stevenson FK, Ottensmeier CH, Rice J (2010) DNA vaccines against cancer come of age. Curr Opin Immunol 22(2):264–270

    Article  CAS  PubMed  Google Scholar 

  25. Hömberg N, Adam C, Riedel T, Brenner C, Flatley A, Röcken M et al (2014) CD40-independent NK-cell help promotes dendritic cell vaccine-induced T-cell immunity against endogenous B-cell lymphoma. Int J Cancer 135(12):2825–2833

    Article  PubMed  Google Scholar 

  26. Bauer C, Sterzik A, Bauernfeind F, Duewell P, Conrad C, Kiefl R et al (2014) Concomitant gemcitabine therapy negatively affects DC vaccine-induced CD8(+) T-cell and B-cell responses but improves clinical efficacy in a murine pancreatic carcinoma model. Cancer Immunol Immunother 63(4):321–333

    Article  CAS  PubMed  Google Scholar 

  27. Domingos-Pereira S, Decrausaz L, Derré L, Bobst M, Romero P, Schiller JT et al (2013) Intravaginal TLR agonists increase local vaccine-specific CD8+ T cells and human papillomavirus-associated genital-tumor regression in mice. Mucosal Immunol 6(2):393–404

    Article  CAS  PubMed  Google Scholar 

  28. Ponsaerts P, Van Tendeloo VF, Berneman ZN (2003) Cancer immunotherapy using RNA-loaded dendritic cells. Clin Exp Immunol 134(3):378–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Geall AJ, Mandl CW, Ulmer JB (2013) RNA: the new revolution in nucleic acid vaccines. Semin Immunol 25(2):152–159

    Article  CAS  PubMed  Google Scholar 

  30. Markov OO, Mironova NL, Maslov MA, Petukhov IA, Morozova NG, Vlassov VV et al (2012) Novel cationic liposomes provide highly efficient delivery of DNA and RNA into dendritic cell progenitors and their immature offsets. J Control Release 160(2):200–210

    Article  CAS  PubMed  Google Scholar 

  31. Garg NK, Dwivedi P, Prabha P, Tyagi RK (2012) RNA pulsed dendritic cells: an approach for cancer immunotherapy. Curr Cancer Drug Targets 31(8):1141–1156

    Google Scholar 

  32. Sebastian KP, Mustafa DP, Abderraouf SP, Özlem TP, Ugur S (2011) Tumor vaccination using messenger RNA: prospects of a future therapy. Curr Opin Immunol 23(3):399–406

    Article  Google Scholar 

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Authors and Affiliations

  1. Institute of Hematology, The Second Affiliate Hospital of Nanchang University, Nanchang, 330000, China

    Li Yu, Ting Hu, Tian Zou & Qingzhi Shi

  2. Institute of Hematology, The First Affiliate Hospital of Nanchang University, Nanchang, 330000, China

    Guoan Chen

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  1. Li Yu
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  2. Ting Hu
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  3. Tian Zou
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  4. Qingzhi Shi
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Correspondence to Li Yu.

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Yu, L., Hu, T., Zou, T. et al. Chronic Myelocytic Leukemia (CML) Patient-Derived Dendritic Cells Transfected with Autologous Total RNA Induces CML-Specific Cytotoxicity. Indian J Hematol Blood Transfus 32, 397–404 (2016). https://doi.org/10.1007/s12288-016-0643-5

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  • DOI: https://doi.org/10.1007/s12288-016-0643-5

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