Skip to main content

Advertisement

SpringerLink
Log in

A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

HLA-mismatched natural killer (NK) cells have shown efficacy in acute myeloid leukemia, and their adoptive transfer in patients with other malignancies has been proven safe. This phase I clinical trial was designed to evaluate safety (primary endpoint) and possible clinical efficacy (secondary endpoint) of repetitive administrations of allogeneic, in vitro activated and expanded NK cells along with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients with unresectable, locally advanced/metastatic NSCLC receiving 1st/2nd line chemotherapy were eligible to receive 2–4 doses of activated NK cells from two relative donors. Donor’s CD56+ cells were cultured for 20–23 days with interleukin-15 (IL-15) and hydrocortisone (HC) and administered intravenously between chemotherapy cycles. Premedication with corticosteroids and/or H1 inhibitors was allowed. Sixteen patients (performance status 0–1) with adenocarcinoma (n = 13) or squamous cell carcinoma (n = 3) at stage IIIb (n = 5) or IV (n = 11) receiving 1st (n = 13) or 2nd (n = 3) line treatment were enrolled. Fifteen patients received 2–4 doses of allogeneic activated NK cells (0.2–29 × 106/kg/dose, median 4.15 × 106/kg/dose). No side effects (local or systemic) were observed. At a median 22-month follow-up (range, 16.5–26 months) 2 patients with partial response and 6 patients with disease stabilization were recorded. Median progression free survival and overall survival were 5.5 and 15 months, respectively. A 56% 1-year survival and a 19% 2-year survival were recorded. In conclusion, repetitive infusions of allogeneic, in vitro activated and expanded with IL-15/HC NK cells, in combination with chemotherapy are safe and potentially clinically effective.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ruggeri L, Mancusi A, Capanni M, Martelli MF, Velardi A (2005) Exploitation of alloreactive NK cells in adoptive immunotherapy of cancer. Curr Opin Immunol 17:211–217

    Article  CAS  PubMed  Google Scholar 

  2. Ruggeri L, Capanni M, Mancusi A, Perruccio K, Burchielli E, Martelli MF, Velardi A (2005) Natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation. Int J Hematol 81:13–17

    Article  CAS  PubMed  Google Scholar 

  3. Moretta A, Locatelli F, Moretta L (2008) Human NK cells: from HLA class I-specific killer Ig-like receptors to the therapy of acute leukemias. Immunol Rev 224:58–69

    Article  CAS  PubMed  Google Scholar 

  4. Gill S, Olson JA, Negrin RS (2009) Natural killer cells in allogeneic transplantation: effect on engraftment, graft- versus-tumor, and graft-versus-host responses. Biol Blood Marrow Transplant 15:765–776

    Article  CAS  PubMed  Google Scholar 

  5. Ljunggren HG, Malmberg KJ (2007) Prospects for the use of NK cells in immunotherapy of human cancer. Nat Rev Immunol 7:329–339

    Article  CAS  PubMed  Google Scholar 

  6. Malmberg KJ, Bryceson YT, Carlsten M, Andersson S, Bjorklund A, Bjorkstrom NK, Baumann BC, Fauriat C, Alici E, Dilber MS, Ljunggren HG (2008) NK cell-mediated targeting of human cancer and possibilities for new means of immunotherapy. Cancer Immunol Immunother 57:1541–1552

    Article  CAS  PubMed  Google Scholar 

  7. Ruggeri L, Mancusi A, Burchielli E, Capanni M, Carotti A, Aloisi T, Aversa F, Martelli MF, Velardi A (2008) NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation. Blood Cells Mol Dis 40:84–90

    Article  CAS  PubMed  Google Scholar 

  8. Slavin S, Ackerstein A, Or R, Shapira MY, Gesundheit B, Askenasy N, Morecki S (2010) Immunotherapy in high-risk chemotherapy-resistant patients with metastatic solid tumors and hematological malignancies using intentionally mismatched donor lymphocytes activated with rIL-2: a phase I study. Cancer Immunol Immunother 59:1511–1519

    Article  CAS  PubMed  Google Scholar 

  9. Carlsten M, Malmberg KJ, Ljunggren HG (2009) Natural killer cell-mediated lysis of freshly isolated human tumor cells. Int J Cancer 124:757–762

    Article  CAS  PubMed  Google Scholar 

  10. De Santis D, Bishara A, Witt CS, Nagler A, Brautbar C, Slavin S, Christiansen FT (2005) Natural killer cell HLA-C epitopes and killer cell immunoglobulin-like receptors both influence outcome of mismatched unrelated donor bone marrow transplants. Tissue Antigens 65:519–528

    Article  PubMed  Google Scholar 

  11. Re F, Staudacher C, Zamai L, Vecchio V, Bregni M (2006) Killer cell Ig-like receptors ligand-mismatched, alloreactive natural killer cells lyse primary solid tumors. Cancer 107:640–648

    Article  CAS  PubMed  Google Scholar 

  12. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB (2005) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105:3051–3057

    Article  CAS  PubMed  Google Scholar 

  13. Berg M, Lundqvist A, McCoy P Jr, Samsel L, Fan Y, Tawab A, Childs R (2009) Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells. Cytotherapy 11:341–355

    Article  CAS  PubMed  Google Scholar 

  14. Berg M, Lundqvist A, Betters D, Childs RW (2009) In vitro expanded NK cells have increased natural cytotoxity receptors, TRAIL and NKG2D expression, and superior tumor cytotoxicity compared to short-term IL-2-activated NK cells. Blood 114:463 (ASH Annual Meeting Abstracts)

    Google Scholar 

  15. Albertsson PA, Basse PH, Hokland M, Goldfarb RH, Nagelkerke JF, Nannmark U, Kuppen PJ (2003) NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. Trends Immunol 24:603–609

    Article  CAS  PubMed  Google Scholar 

  16. Brand JM, Meller B, Von Hof K, Luhm J, Bahre M, Kirchner H, Frohn C (2004) Kinetics and organ distribution of allogeneic natural killer lymphocytes transfused into patients suffering from renal cell carcinoma. Stem Cells Dev 13:307–314

    Article  CAS  PubMed  Google Scholar 

  17. Zhang T, Herlyn D (2009) Combination of active specific immunotherapy or adoptive antibody or lymphocyte immunotherapy with chemotherapy in the treatment of cancer. Cancer Immunol Immunother 58:475–492

    Article  CAS  PubMed  Google Scholar 

  18. Baxevanis CN, Perez SA, Papamichail M (2009) Combinatorial treatments including vaccines, chemotherapy and monoclonal antibodies for cancer therapy. Cancer Immunol Immunother 58:317–324

    Article  PubMed  Google Scholar 

  19. Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis E, Gabrilovich DI (2010) Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest 120:1111–1124

    Article  CAS  PubMed  Google Scholar 

  20. Perez SA, Mahaira LG, Demirtzoglou FJ, Sotiropoulou PA, Ioannidis P, Iliopoulou EG, Gritzapis AD, Sotiriadou NN, Baxevanis CN, Papamichail M (2005) A potential role for hydrocortisone in the positive regulation of IL-15-activated NK-cell proliferation and survival. Blood 106:158–166

    Article  CAS  PubMed  Google Scholar 

  21. Sato N, Patel HJ, Waldmann TA, Tagaya Y (2007) The IL-15/IL-15Ralpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc Natl Acad Sci USA 104:588–593

    Article  CAS  PubMed  Google Scholar 

  22. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  23. Crivellari G, Monfardini S, Stragliotto S, Marino D, Aversa SM (2007) Increasing chemotherapy in small-cell lung cancer: from dose intensity and density to megadoses. Oncologist 12:79–89

    Article  CAS  PubMed  Google Scholar 

  24. Becknell B, Caligiuri MA (2005) Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol 86:209–239

    Article  CAS  PubMed  Google Scholar 

  25. Reiche EM, Nunes SO, Morimoto HK (2004) Stress, depression, the immune system, and cancer. Lancet Oncol 5:617–625

    Article  CAS  PubMed  Google Scholar 

  26. Nannmark U, Hokland ME, Agger R, Christiansen M, Kjaergaard J, Goldfarb RH, Bagge U, Unger M, Johansson BR, Albertsson PA, Basse PH (2000) Tumor blood supply and tumor localization by adoptively transferred IL-2 activated natural killer cells. In Vivo 14:651–658

    CAS  PubMed  Google Scholar 

  27. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98

    Article  CAS  PubMed  Google Scholar 

  28. Sculier JP, Moro-Sibilot D (2009) First- and second-line therapy for advanced nonsmall cell lung cancer. Eur Respir J 33:915–930

    Article  CAS  PubMed  Google Scholar 

  29. Andoniou CE, Coudert JD, Degli-Esposti MA (2008) Killers and beyond: NK-cell-mediated control of immune responses. Eur J Immunol 38:2938–2942

    Article  CAS  PubMed  Google Scholar 

  30. Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA (2004) NK cell and DC interactions. Trends Immunol 25:47–52

    Article  CAS  PubMed  Google Scholar 

  31. Moretta L, Ferlazzo G, Bottino C, Vitale M, Pende D, Mingari MC, Moretta A (2006) Effector and regulatory events during natural killer-dendritic cell interactions. Immunol Rev 214:219–228

    Article  CAS  PubMed  Google Scholar 

  32. Ghiringhelli F, Apetoh L, Housseau F, Kroemer G, Zitvogel L (2007) Links between innate and cognate tumor immunity. Curr Opin Immunol 19:224–231

    Article  CAS  PubMed  Google Scholar 

  33. Krebs P, Barnes MJ, Lampe K, Whitley K, Bahjat KS, Beutler B, Janssen E, Hoebe K (2009) NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses. Blood 113:6593–6602

    Article  CAS  PubMed  Google Scholar 

  34. Hanna J, Gonen-Gross T, Fitchett J, Rowe T, Daniels M, Arnon TI, Gazit R, Joseph A, Schjetne KW, Steinle A, Porgador A, Mevorach D, Goldman-Wohl D, Yagel S, LaBarre MJ, Buckner JH, Mandelboim O (2004) Novel APC-like properties of human NK cells directly regulate T cell activation. J Clin Invest 114:1612–1623

    CAS  PubMed  Google Scholar 

  35. Barber LD, Madrigal JA (2006) Exploiting beneficial alloreactive T cells. Vox Sang 91:20–27

    Article  CAS  PubMed  Google Scholar 

  36. Ramakrishnan R, Antonia S, Gabrilovich DI (2008) Combined modality immunotherapy and chemotherapy: a new perspective. Cancer Immunol Immunother 57:1523–1529

    Article  CAS  PubMed  Google Scholar 

  37. Schlom J, Arlen PM, Gulley JL (2007) Cancer vaccines: moving beyond current paradigms. Clin Cancer Res 13:3776–3782

    Article  CAS  PubMed  Google Scholar 

  38. Kosmidis PA, Kalofonos HP, Christodoulou C, Syrigos K, Makatsoris T, Skarlos D, Bakogiannis C, Nicolaides C, Bafaloukos D, Bamias A, Samantas E, Xiros N, Boukovinas I, Fountzilas G, Dimopoulos MA (2008) Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol 19:115–122

    Article  CAS  PubMed  Google Scholar 

  39. Scagliotti GV, De Marinis F, Rinaldi M, Crino L, Gridelli C, Ricci S, Matano E, Boni C, Marangolo M, Failla G, Altavilla G, Adamo V, Ceribelli A, Clerici M, Di Costanzo F, Frontini L, Tonato M (2002) Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 20:4285–4291

    Article  CAS  PubMed  Google Scholar 

  40. D’Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA (2005) Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 23:2926–2936

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are indebted to our patients and their relatives for their voluntary participation in this study as well as to the nurses at the Outpatient Unit of Saint Savas Cancer Hospital for taking care of patients. We also thank all the staff of the Biochemistry, the Microbiology, and the Hematology Departments of our Hospital for helping in the accomplishment of this trial and Ms Joanne Kalogeropoulou for excellent technical assistance. Supported by Regional Operational Program Attika no. 20 MIS code 59605 G.R. to M.P.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 115 22, Athens, Greece

    Eleni G. Iliopoulou, Constantin N. Baxevanis, Michael Papamichail & Sonia A. Perez

  2. First Department of Medical Oncology, Saint Savas Cancer Hospital, Athens, Greece

    Panteleimon Kountourakis, Michalis V. Karamouzis, Dimitrios Doufexis, Alexandros Ardavanis & Gerasimos Rigatos

  3. Medical Oncology Department, Bank of Cyprus Oncology Centre, Nicosia, Cyprus

    Panteleimon Kountourakis

  4. Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece

    Michalis V. Karamouzis

Authors
  1. Eleni G. Iliopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Panteleimon Kountourakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michalis V. Karamouzis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dimitrios Doufexis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexandros Ardavanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Constantin N. Baxevanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gerasimos Rigatos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Papamichail
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sonia A. Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sonia A. Perez.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 36 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iliopoulou, E.G., Kountourakis, P., Karamouzis, M.V. et al. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol Immunother 59, 1781–1789 (2010). https://doi.org/10.1007/s00262-010-0904-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0904-3

Keywords

Search

Navigation