Advertisement

Interleukin-2: Old and New Approaches to Enhance Immune-Therapeutic Efficacy

  • Pooja Dhupkar
  • Nancy Gordon
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 995)

Abstract

Interleukin-2 (IL-2) is a very well-known cytokine that has been studied for the past 35 years. It plays a major role in the growth and proliferation of many immune cells such NK and T cells. It is an important immunotherapy cytokine for the treatment of various diseases including cancer. Systemic delivery of IL-2 has shown clinical benefit in renal cell carcinoma and melanoma patients. However, its use has been limited by the numerous toxicities encountered with the systemic delivery. Intravenous IL-2 causes the well-known “capillary leak syndrome,” or the leakage of fluid from the circulatory system to the interstitial space resulting in hypotension (low blood pressure), edema, and dyspnea that can lead to circulatory shock and eventually cardiopulmonary collapse and multiple organ failure. Due to the toxicities associated with systemic IL-2, an aerosolized delivery approach has been developed, which enables localized delivery and a higher local immune cell activation. Since proteins are absorbed via pulmonary lymphatics, after aerosol deposition in the lung, aerosol delivery provides a means to more specifically target IL-2 to the local immune system in the lungs with less systemic effects. Its benefits have extended to diseases other than cancer. Delivery of IL-2 via aerosol or as nebulized IL-2 liposomes has been previously shown to have less toxicity and higher efficacy against sarcoma lung metastases. Dogs with cancer provided a highly relevant means to determine biodistribution of aerosolized IL-2 and IL-2 liposomes. However, efficacy of single-agent IL-2 is limited. As in general, for most immune-therapies, its effect is more beneficial in the face of minimal residual disease. To overcome this limitation, combination therapies using aerosol IL-2 with adoptive transfer of T cells or NK cells have emerged.

Using a human osteosarcoma (OS) mouse model, we have demonstrated the efficacy of single-agent aerosol IL-2 and combination therapy aerosol IL-2 and NK cells or aerosol IL-2 and interleukin 11 receptor alpha-directed chimeric antigen receptor-T cells (IL-11 receptor α CAR-T cells) against OS pulmonary metastases. Combination therapy resulted in a better therapeutic effect. A Phase-I trial of aerosol IL-2 was done in Europe and proved to be safe. Others and our preclinical studies provided the basis for the development of a Phase-I aerosol IL-2 trial in our institution to include younger patients with lung metastases. OS, our disease of interest, has a peak incidence in the adolescent and young adult years. Our goal is to complete this trial in the next 2 years.

In this chapter, we summarize the different effects of IL-2 and cover the advantages of the aerosol delivery route for diseases of the lung with an emphasis on some of our most recent work using combination therapy aerosol IL-2 and NK cells for the treatment of OS lung metastases.

Keywords

Aerosol IL-2 Osteosarcoma Immunotherapy Lung metastasis NK cell therapy IL-2 clinical trial 

Notes

Acknowledgements

The authors would like to acknowledge Dr. Eugenie S. Kleinerman for her continuous mentorship, encouragement, and support and Dr. Sergei R. Guma for allowing us to share some of his studies to further inform the scientific community.

References

  1. 1.
    Taniguchi T, Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell. 1993;73(1):5–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Lotze MT, et al. In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2. J Immunol. 1985;134(1):157–66.PubMedGoogle Scholar
  3. 3.
    Lotze MT, et al. In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J Immunol. 1985;135(4):2865–75.PubMedGoogle Scholar
  4. 4.
    Parkinson DR. Interleukin-2 in cancer therapy. Semin Oncol. 1988;15(6 Suppl 6):10–26.PubMedGoogle Scholar
  5. 5.
    Rosenberg SA, et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985;161(5):1169–88.CrossRefPubMedGoogle Scholar
  6. 6.
    D’Angelo SP, et al. Sarcoma immunotherapy: past approaches and future directions. Sarcoma. 2014;2014:391967.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Fagan EA, Eddleston AL. Immunotherapy for cancer: the use of lymphokine activated killer (LAK) cells. Gut. 1987;28(2):113–6.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Grimm EA, et al. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155(6):1823–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Yang SC, et al. Clinical and immunomodulatory effects of combination immunotherapy with low-dose interleukin 2 and tumor necrosis factor alpha in patients with advanced non-small cell lung cancer: a phase I trial. Cancer Res. 1991;51(14):3669–76.PubMedGoogle Scholar
  10. 10.
    Yang SC, et al. Induction of lymphokine-activated killer cytotoxicity with interleukin-2 and tumor necrosis factor-alpha against primary lung cancer targets. Cancer Immunol Immunother. 1989;29(3):193–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Rosenberg SA, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst. 1993;85(8):622–32.CrossRefPubMedGoogle Scholar
  12. 12.
    Mazumder A, Rosenberg SA. Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin 2. J Exp Med. 1984;159(2):495–507.CrossRefPubMedGoogle Scholar
  13. 13.
    Mule JJ, et al. Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science. 1984;225(4669):1487–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Mule JJ, Shu S, Rosenberg SA. The anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo. J Immunol. 1985;135(1):646–52.PubMedGoogle Scholar
  15. 15.
    Lafreniere R, Rosenberg SA. Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2. Cancer Res. 1985;45(8):3735–41.PubMedGoogle Scholar
  16. 16.
    Lafreniere R, Rosenberg SA. Adoptive immunotherapy of murine hepatic metastases with lymphokine activated killer (LAK) cells and recombinant interleukin 2 (RIL 2) can mediate the regression of both immunogenic and nonimmunogenic sarcomas and an adenocarcinoma. J Immunol. 1985;135(6):4273–80.PubMedGoogle Scholar
  17. 17.
    Rosenberg SA, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313(23):1485–92.CrossRefPubMedGoogle Scholar
  18. 18.
    Rosenberg SA, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907–13.CrossRefPubMedGoogle Scholar
  19. 19.
    Atkins MB, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.CrossRefPubMedGoogle Scholar
  20. 20.
    Kruit WH, et al. Dose efficacy study of two schedules of high-dose bolus administration of interleukin 2 and interferon alpha in metastatic melanoma. Br J Cancer. 1996;74(6):951–5.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Keilholz U, et al. Interferon-alpha and interleukin-2 in the treatment of metastatic melanoma. Comparison of two phase II trials. Cancer. 1993;72(2):607–14.CrossRefPubMedGoogle Scholar
  22. 22.
    de Gast GC, et al. Phase I trial of combined immunotherapy with subcutaneous granulocyte macrophage colony-stimulating factor, low-dose interleukin 2, and interferon alpha in progressive metastatic melanoma and renal cell carcinoma. Clin Cancer Res. 2000;6(4):1267–72.PubMedGoogle Scholar
  23. 23.
    Dutcher JP, et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am. 1997;3(Suppl 1):S73–8.PubMedGoogle Scholar
  24. 24.
    Rosenberg SA, et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989; 210(4):474–84; discussion 484–5.Google Scholar
  25. 25.
    Schwinger W, et al. Feasibility of high-dose interleukin-2 in heavily pretreated pediatric cancer patients. Ann Oncol. 2005;16(7):1199–206.CrossRefPubMedGoogle Scholar
  26. 26.
    Rosenstein M, Ettinghausen SE, Rosenberg SA. Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin-2. J Immunol. 1986;137(5):1735–42.PubMedGoogle Scholar
  27. 27.
    Panelli MC, et al. Forecasting the cytokine storm following systemic interleukin (IL)-2 administration. J Transl Med. 2004;2(1):17.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lotze MT, et al. Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer. 1986;58(12):2764–72.CrossRefPubMedGoogle Scholar
  29. 29.
    Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180–90.PubMedGoogle Scholar
  30. 30.
    Boyman O, Surh CD, Sprent J. Potential use of IL-2/anti-IL-2 antibody immune complexes for the treatment of cancer and autoimmune disease. Expert Opin Biol Ther. 2006;6(12):1323–31.CrossRefPubMedGoogle Scholar
  31. 31.
    Schuchter LM, et al. Eosinophilic myocarditis associated with high-dose interleukin-2 therapy. Am J Med. 1990;88(4):439–40.CrossRefPubMedGoogle Scholar
  32. 32.
    Klempner MS, et al. An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N Engl J Med. 1990;322(14):959–65.CrossRefPubMedGoogle Scholar
  33. 33.
    Donohue JH, Rosenberg SA. The fate of interleukin-2 after in vivo administration. J Immunol. 1983;130(5):2203–8.PubMedGoogle Scholar
  34. 34.
    Shaker MA, Younes HM. Interleukin-2: evaluation of routes of administration and current delivery systems in cancer therapy. J Pharm Sci. 2009;98(7):2268–98.CrossRefPubMedGoogle Scholar
  35. 35.
    Konrad MW, et al. Pharmacokinetics of recombinant interleukin 2 in humans. Cancer Res. 1990;50(7):2009–17.PubMedGoogle Scholar
  36. 36.
    Anderson PM, Sorenson MA. Effects of route and formulation on clinical pharmacokinetics of interleukin-2. Clin Pharmacokinet. 1994;27(1):19–31.CrossRefPubMedGoogle Scholar
  37. 37.
    Kammula US, White DE, Rosenberg SA. Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer. 1998;83(4):797–805.CrossRefPubMedGoogle Scholar
  38. 38.
    Khanna C, et al. Interleukin-2 liposome inhalation therapy is safe and effective for dogs with spontaneous pulmonary metastases. Cancer. 1997;79(7):1409–21.CrossRefPubMedGoogle Scholar
  39. 39.
    Khanna C, et al. Nebulized interleukin 2 liposomes: aerosol characteristics and biodistribution. J Pharm Pharmacol. 1997;49(10):960–71.CrossRefPubMedGoogle Scholar
  40. 40.
    Dow S, et al. Phase I study of liposome-DNA complexes encoding the interleukin-2 gene in dogs with osteosarcoma lung metastases. Hum Gene Ther. 2005;16(8):937–46.CrossRefPubMedGoogle Scholar
  41. 41.
    Rabinovitch A, et al. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes. 2002;51(3):638–45.CrossRefPubMedGoogle Scholar
  42. 42.
    Shin JI, Park SJ, Kim JH. A possible role of leptin-associated increase in soluble interleukin-2 receptor diminishing a clinical response to infliximab in rheumatoid arthritis: comment on the article by Klaasen et al. Arthritis Rheum. 2011;63(9):2833–4; author reply 2834.Google Scholar
  43. 43.
    Tomala J, et al. In vivo expansion of activated naive CD8+ T cells and NK cells driven by complexes of IL-2 and anti-IL-2 monoclonal antibody as novel approach of cancer immunotherapy. J Immunol. 2009;183(8):4904–12.CrossRefPubMedGoogle Scholar
  44. 44.
    Votavova P, Tomala J, Kovar M. Increasing the biological activity of IL-2 and IL-15 through complexing with anti-IL-2 mAbs and IL-15Ralpha-Fc chimera. Immunol Lett. 2014;159(1–2):1–10.CrossRefPubMedGoogle Scholar
  45. 45.
    Krieg C, et al. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci U S A. 2010;107(26):11906–11.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Letourneau S, et al. IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25. Proc Natl Acad Sci U S A. 2010;107(5):2171–6.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Levin AM, et al. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature. 2012;484(7395):529–33.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Rojas G, et al. Deciphering the molecular bases of the biological effects of antibodies against interleukin-2: a versatile platform for fine epitope mapping. Immunobiology. 2013;218(1):105–13.CrossRefPubMedGoogle Scholar
  49. 49.
    Rojas G, et al. Fine epitope specificity of antibodies against interleukin-2 explains their paradoxical immunomodulatory effects. MAbs. 2014;6(1):273–85.CrossRefPubMedGoogle Scholar
  50. 50.
    Carmenate T, et al. Human IL-2 mutein with higher antitumor efficacy than wild type IL-2. J Immunol. 2013;190(12):6230–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Rotte A, et al. Immunotherapy of melanoma: present options and future promises. Cancer Metastasis Rev. 2015;34(1):115–28.CrossRefPubMedGoogle Scholar
  52. 52.
    Gillies SD, et al. A low-toxicity IL-2-based immunocytokine retains antitumor activity despite its high degree of IL-2 receptor selectivity. Clin Cancer Res. 2011;17(11):3673–85.CrossRefPubMedGoogle Scholar
  53. 53.
    Gubbels JA, et al. Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface. Cancer Immunol Immunother. 2011;60(12):1789–800.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Gillessen S, et al. A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours. Eur J Cancer. 2013;49(1):35–44.CrossRefPubMedGoogle Scholar
  55. 55.
    Klein C. Novel CEA-targeted IL-2 variant immunocytokine for immunotherapy of cancer. J ImmunoTherapy Cancer. 2014;2(Suppl 2):18.CrossRefGoogle Scholar
  56. 56.
    Hank JA, et al. Immunogenicity of the hu14.18-IL2 immunocytokine molecule in adults with melanoma and children with neuroblastoma. Clin Cancer Res. 2009;15(18):5923–30.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Shusterman S, et al. Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children’s Oncology Group (COG) phase II study. J Clin Oncol. 2010;28(33):4969–75.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Sharma S, et al. Development of inhalational agents for oncologic use. J Clin Oncol. 2001;19(6):1839–47.CrossRefPubMedGoogle Scholar
  59. 59.
    Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):583–92.CrossRefPubMedGoogle Scholar
  60. 60.
    Gagnadoux F, et al. Aerosolized chemotherapy. J Aerosol Med Pulm Drug Deliv. 2008;21(1):61–70.CrossRefPubMedGoogle Scholar
  61. 61.
    Merimsky O, et al. Targeting pulmonary metastases of renal cell carcinoma by inhalation of interleukin-2. Ann Oncol. 2004;15(4):610–2.CrossRefPubMedGoogle Scholar
  62. 62.
    Lorenz J, et al. Phase I trial of inhaled natural interleukin 2 for treatment of pulmonary malignancy: toxicity, pharmacokinetics, and biological effects. Clin Cancer Res. 1996;2(7):1115–22.PubMedGoogle Scholar
  63. 63.
    Guma SR, et al. Aerosol interleukin-2 induces natural killer cell proliferation in the lung and combination therapy improves the survival of mice with osteosarcoma lung metastasis. Pediatr Blood Cancer. 2014;61(8):1362–8.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Guma SR, et al. Natural killer cell therapy and aerosol interleukin-2 for the treatment of osteosarcoma lung metastasis. Pediatr Blood Cancer. 2014;61(4):618–26.CrossRefPubMedGoogle Scholar
  65. 65.
    Huang GX, et al. Genetically modified T cells targeting interleukin-11 receptor alpha-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. Cancer Res. 2012;72(1):271–81.CrossRefPubMedGoogle Scholar
  66. 66.
    Atkins MB, et al. Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol. 1993;11(4):661–70.CrossRefPubMedGoogle Scholar
  67. 67.
    Sparano JA, et al. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993;11(10):1969–77.CrossRefPubMedGoogle Scholar
  68. 68.
    Keilholz U, et al. Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients. J Clin Oncol. 1998;16(9):2921–9.CrossRefPubMedGoogle Scholar
  69. 69.
    van Herpen CM, et al. Immunochemotherapy with interleukin-2, interferon-alpha and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study. Dutch Immunotherapy Working Party. Br J Cancer. 2000;82(4):772–6.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Tarhini AA, et al. A phase 2 trial of sequential temozolomide chemotherapy followed by high-dose interleukin 2 immunotherapy for metastatic melanoma. Cancer. 2008;113(7):1632–40.CrossRefPubMedGoogle Scholar
  71. 71.
    Panares RL, Garcia AA. Bevacizumab in the management of solid tumors. Expert Rev Anticancer Ther. 2007;7(4):433–45.CrossRefPubMedGoogle Scholar
  72. 72.
    Bakker AB, et al. Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. J Exp Med. 1994;179(3):1005–9.CrossRefPubMedGoogle Scholar
  73. 73.
    Smith FO, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14(17):5610–8.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Kaufman HL, et al. Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high dose interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma. J Transl Med. 2009;7:2.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Block MS, et al. Pilot study of granulocyte-macrophage colony-stimulating factor and interleukin-2 as immune adjuvants for a melanoma peptide vaccine. Melanoma Res. 2011;21(5):438–45.CrossRefPubMedGoogle Scholar
  76. 76.
    Dudley ME, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233–9.CrossRefPubMedCentralGoogle Scholar
  77. 77.
    Dudley ME, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298(5594):850–4.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12(4):269–81.CrossRefPubMedGoogle Scholar
  79. 79.
    Radvanyi LG, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2012;18(24):6758–70.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Besser MJ, et al. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients. J Immunother. 2009;32(4):415–23.CrossRefPubMedGoogle Scholar
  81. 81.
    Besser MJ, et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2010;16(9):2646–55.CrossRefPubMedGoogle Scholar
  82. 82.
    Ellebaek E, et al. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose interleukin-2 in metastatic melanoma patients. J Transl Med. 2012;10:169.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Huang G, et al. Genetically modified T cells targeting interleukin-11 receptor alpha-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. Cancer Res. 2012;72(1):271–81.CrossRefPubMedGoogle Scholar
  84. 84.
    Garg TK, et al. Highly activated and expanded natural killer cells for multiple myeloma immunotherapy. Haematologica. 2012;97(9):1348–56.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Fujisaki H, et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009;69(9):4010–7.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Denman CJ, et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One. 2012;7(1):e30264.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Krause SW, et al. Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase i trial. Clin Cancer Res. 2004;10(11):3699–707.CrossRefPubMedGoogle Scholar
  88. 88.
    Parkhurst MR, et al. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res. 2011;17(19):6287–97.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Ruggeri L, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295(5562):2097–100.CrossRefPubMedGoogle Scholar
  90. 90.
    Miller JS, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105(8):3051–7.CrossRefPubMedGoogle Scholar
  91. 91.
    Curti A, et al. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood. 2011;118(12):3273–9.CrossRefPubMedGoogle Scholar
  92. 92.
    Iliopoulou EG, 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. 2010;59(12):1781–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Pediatrics-ResearchThe Children’s Cancer Hospital, University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Experimental Therapeutics Academic ProgramThe University of Texas Health Science Center at HoustonHoustonUSA

Personalised recommendations