Top

Published in:

01-05-2015 | Original Article

Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma

Authors: Diana Seidel, Anastasia Shibina, Nikolai Siebert, Winfried S. Wels, C. Patrick Reynolds, Nicole Huebener, Holger N. Lode

Published in: Cancer Immunology, Immunotherapy | Issue 5/2015

Abstract

The disialoganglioside GD2 is a well-established target antigen for passive immunotherapy in neuroblastoma (NB). Despite the recent success of passive immunotherapy with the anti-GD2 antibody ch14.18 and cytokines, treatment of high-risk NB remains challenging. We expanded the approach of GD2-specific, antibody-based immunotherapy to an application of a GD2-specific natural killer (NK) cell line, NK-92-scFv(ch14.18)-zeta. NK-92-scFv(ch14.18)-zeta is genetically engineered to express a GD2-specific chimeric antigen receptor generated from ch14.18. Here, we show that chimeric receptor expression enables NK-92-scFv(ch14.18)-zeta to effectively lyse GD2⁺ NB cells also including partially or multidrug-resistant lines. Our data suggest that recognition of GD2 by the chimeric receptor is the primary mechanism involved in NK-92-scFv(ch14.18)-zeta-mediated lysis and is independent of activating NK cell receptor/ligand interactions. Furthermore, we demonstrate that NK-92-scFv(ch14.18)-zeta is able to mediate a significant anti-tumor response in vivo in a drug-resistant GD2⁺ NB xenograft mouse model. NK-92-scFv(ch14.18)-zeta is an NB-specific NK cell line that has potential for future clinical development due to its high stability and activity toward GD2⁺ NB cell lines.

Westermann F, Schwab M (2002) Genetic parameters of neuroblastomas. Cancer Lett 184:127–147CrossRefPubMed

Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. Lancet 369:2106–2120CrossRefPubMed

van Noesel MM, Versteeg R (2004) Pediatric neuroblastomas: genetic and epigenetic ‘danse macabre’. Gene 325:1–15CrossRefPubMed

Keshelava N, Seeger RC, Groshen S, Reynolds CP (1998) Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res 58:5396–5405PubMed

Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM (2010) Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363:1324–1334CrossRefPubMedCentralPubMed

Mujoo K, Cheresh DA, Yang HM, Reisfeld RA (1987) Disialoganglioside GD2 on human neuroblastoma cells: target antigen for monoclonal antibody-mediated cytolysis and suppression of tumor growth. Cancer Res 47:1098–1104PubMed

Yang RK, Sondel PM (2010) Anti-GD2 strategy in the treatment of neuroblastoma. Drugs Future 35:665CrossRefPubMedCentralPubMed

Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220CrossRefPubMed

Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47:187–376CrossRefPubMed

10.

Cullen SP, Martin SJ (2008) Mechanisms of granule-dependent killing. Cell Death Differ 15:251–262CrossRefPubMed

11.

Schmitz I, Kirchhoff S, Krammer PH (2000) Regulation of death receptor-mediated apoptosis pathways. Int J Biochem Cell Biol 32:1123–1136CrossRefPubMed

12.

Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM (2000) In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA 97:2731–2736CrossRefPubMedCentralPubMed

13.

Gong JH, Maki G, Klingemann HG (1994) Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8:652–658PubMed

14.

Klingemann HG, Wong E, Maki G (1996) A cytotoxic NK-cell line (NK-92) for ex vivo purging of leukemia from blood. Biol Blood Marrow Transplant 2:68–75PubMed

15.

Tam YK, Martinson JA, Doligosa K, Klingemann HG (2003) Ex vivo expansion of the highly cytotoxic human natural killer-92 cell-line under current good manufacturing practice conditions for clinical adoptive cellular immunotherapy. Cytotherapy 5:259–272CrossRefPubMed

16.

Yan Y, Steinherz P, Klingemann HG, Dennig D, Childs BH, McGuirk J, O’Reilly RJ (1998) Antileukemia activity of a natural killer cell line against human leukemias. Clin Cancer Res 4(11):2859–2868PubMed

17.

Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, Klingemann H (2008) Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 10(6):625–632CrossRefPubMed

18.

Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U, Suttorp M, Seifried E, Ottmann OG, Bug G (2013) Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 15(12):1563–1570CrossRefPubMed

19.

Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419:734–738CrossRefPubMed

20.

Lee JC, Lee KM, Kim DW, Heo DS (2004) Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172:7335–7340CrossRefPubMed

21.

Uherek C, Groner B, Wels W (2001) Chimeric antigen receptors for the retargeting of cytotoxic effector cells. J Hematother Stem Cell Res 10:523–534CrossRefPubMed

22.

Esser R, Muller T, Stefes D, Kloess S, Seidel D, Gillies SD, Aperlo-Iffland C, Huston JS, Uherek C, Schonfeld K, Tonn T, Huebener N, Lode HN, Koehl U, Wels WS (2012) NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. J Cell Mol Med 16(3):569–581CrossRefPubMedCentralPubMed

23.

Keshelava N, Zuo JJ, Chen P, Waidyaratne SN, Luna MC, Gomer CJ, Triche TJ, Reynolds CP (2001) Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines. Cancer Res 61(16):6185–6193PubMed

24.

Keshelava N, Davicioni E, Wan Z, Ji L, Sposto R, Triche TJ, Reynolds CP (2007) Histone deacetylase 1 gene expression and sensitization of multidrug-resistant neuroblastoma cell lines to cytotoxic agents by depsipeptide. J Natl Cancer Inst 99(14):1107–1119CrossRefPubMed

25.

Uherek C, Tonn T, Uherek B, Becker S, Schnierle B, Klingemann HG, Wels W (2002) Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood 100(4):1265–1273PubMed

26.

Lode HN, Schmidt M, Seidel D, Huebener N, Brackrock D, Bleeke M, Reker D, Brandt S, Mueller HP, Helm C, Siebert N (2013) Vaccination with anti-idiotype antibody ganglidiomab mediates a GD(2)-specific anti-neuroblastoma immune response. Cancer Immunol Immunother 62(6):999–1010CrossRefPubMed

27.

Raffaghello L, Prigione I, Airoldi I, Camoriano M, Morandi F, Bocca P, Gambini C, Ferrone S, Pistoia V (2005) Mechanisms of immune evasion of human neuroblastoma. Cancer Lett 228(1–2):155–161CrossRefPubMed

28.

Farag SS, Fehniger TA, Ruggeri L, Velardi A, Caligiuri MA (2002) Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood 100:1935–1947CrossRefPubMed

29.

Papamichail M, Perez SA, Gritzapis AD, Baxevanis CN (2004) Natural killer lymphocytes: biology, development, and function. Cancer Immunol Immunother 53:176–186CrossRefPubMed

30.

Suck G (2006) Novel approaches using natural killer cells in cancer therapy. Semin Cancer Biol 16:412–418CrossRefPubMed

31.

Sutlu T, Alici E (2009) Natural killer cell-based immunotherapy in cancer: current insights and future prospects. J Intern Med 266:154–181CrossRefPubMed

32.

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

33.

Velardi A, Ruggeri L, Mancusi A, Aversa F, Christiansen FT (2009) Natural killer cell allorecognition of missing self in allogeneic hematopoietic transplantation: a tool for immunotherapy of leukemia. Curr Opin Immunol 21:525–530CrossRefPubMed

34.

Voskens CJ, Watanabe R, Rollins S, Campana D, Hasumi K, Mann DL (2010) Ex-vivo expanded human NK cells express activating receptors that mediate cytotoxicity of allogeneic and autologous cancer cell lines by direct recognition and antibody directed cellular cytotoxicity. J Exp Clin Cancer Res 29:134CrossRefPubMedCentralPubMed

35.

Kloess S, Huenecke S, Piechulek D, Esser R, Koch J, Brehm C, Soerensen J, Gardlowski T, Brinkmann A, Bader P, Passweg J, Klingebiel T, Schwabe D, Koehl U (2010) IL-2-activated haploidentical NK cells restore NKG2D-mediated NK-cell cytotoxicity in neuroblastoma patients by scavenging of plasma MICA. Eur J Immunol 40(11):3255–3267CrossRefPubMed

36.

Altvater B, Landmeier S, Pscherer S, Temme J, Schweer K, Kailayangiri S, Campana D, Juergens H, Pule M, Rossig C (2009) 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clin Cancer Res 15(15):4857–4866CrossRefPubMedCentralPubMed

37.

Imai C, Iwamoto S, Campana D (2005) Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 106:376–383CrossRefPubMedCentralPubMed

38.

Liu Y, Wu HW, Sheard MA, Sposto R, Somanchi SS, Cooper LJ, Lee DA, Seeger RC (2013) Growth and activation of natural killer cells ex vivo from children with neuroblastoma for adoptive cell therapy. Clin Cancer Res 19(8):2132–2143CrossRefPubMedCentralPubMed

39.

Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D (2009) Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res 69(9):4010–4017CrossRefPubMedCentralPubMed

40.

Benjamin JE, Gill S, Negrin RS (2010) Biology and clinical effects of natural killer cells in allogeneic transplantation. Curr Opin Oncol 22(2):130–137CrossRefPubMedCentralPubMed

41.

Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia Frassoni F, Aversa F, Martelli MF, Velardi A (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295(5562):2097–2100CrossRefPubMed

42.

Campbell KS, Hasegawa J (2013) Natural killer cell biology: an update and future directions. J Allergy Clin Immunol 132(3):536–544CrossRefPubMedCentralPubMed

43.

Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365(8):725–733CrossRefPubMedCentralPubMed

44.

Tonn T, Becker S, Esser R, Schwabe D, Seifried E (2001) Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92. J Hematother Stem Cell Res 10:535–544CrossRefPubMed

45.

Muller T, Uherek C, Maki G, Chow KU, Schimpf A, Klingemann HG, Tonn T, Wels WS (2008) Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother 57(3):411–423CrossRefPubMed

Title: Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma
Authors: Diana Seidel
Anastasia Shibina
Nikolai Siebert
Winfried S. Wels
C. Patrick Reynolds
Nicole Huebener
Holger N. Lode
Publication date: 01-05-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 5/2015
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-015-1669-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2015

Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8+ T cells

Intra-adrenal murine TH-MYCN neuroblastoma tumors grow more aggressive and exhibit a distinct tumor microenvironment relative to their subcutaneous equivalents

The safety of allogeneic innate lymphocyte therapy for glioma patients with prior cranial irradiation

NZ28-induced inhibition of HSF1, SP1 and NF-κB triggers the loss of the natural killer cell-activating ligands MICA/B on human tumor cells

Role of NKG2D, DNAM-1 and natural cytotoxicity receptors in cytotoxicity toward rhabdomyosarcoma cell lines mediated by resting and IL-15-activated human natural killer cells

Broadening the repertoire of melanoma-associated T-cell epitopes

Keynote webinar | Spotlight on antibody–drug conjugates in cancer