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Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy

    Zulmarie Perez Horta

    Department of Human Oncology, University of Wisconsin, Madison, WI, USA

    Department of Human Oncology, University of Wisconsin, Madison, WI, USA

    ,
    Jacob L Goldberg

    Department of Human Oncology, University of Wisconsin, Madison, WI, USA

    Department of Human Oncology, University of Wisconsin, Madison, WI, USA

    &
    Paul M Sondel

    *Author for correspondence:

    E-mail Address: pmsondel@humonc.wisc.edu

    Department of Human Oncology, University of Wisconsin, Madison, WI, USA

    Department of Pediatrics & Genetics, University of Wisconsin School of Medicine & Public Health, Madison, WI, USA

    Department of Human Oncology, University of Wisconsin, Madison, WI, USA

    Department of Pediatrics & Genetics, University of Wisconsin School of Medicine & Public Health, Madison, WI, USA

    Published Online:https://doi.org/10.2217/imt-2016-0021

    Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited expression on normal tissue, the GD2 disialogangloside expressed on neuroblastoma cells is an excellent candidate for mAb therapy. In 2015, dinutuximab (an anti-GD2 mAb) was approved by the US FDA and is currently used in a combination immunotherapeutic regimen for the treatment of children with high-risk neuroblastoma. Here, we review the extensive preclinical and clinical development of anti-GD2 mAbs and the different mechanisms by which they mediate tumor cell killing. In addition, we discuss different mAb-based strategies that capitalize on the targeting ability of anti-GD2 mAbs to potentially deliver, as monotherapy, or in combination with other treatments, improved antitumor efficacy.

    References

    • 1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J. Clin. 65(1), 5–29 (2015).
    • 2 Mujoo K, Cheresh DA, Yang HM, Reisfeld RA. Disialoganglioside GD2 on human neuroblastoma cells: target antigen for monoclonal antibody-mediated cytolysis and suppression of tumor growth. Cancer Res. 47(4), 1098–1104 (1987).
    • 3 US FDA. FDA approves first therapy for high-risk neuroblastoma [press release]. 10 March (2015) www.fda.gov/newsevents/newsroom/pressannouncements/ucm437460.htm
    • 4 Cartron G, Dacheux L, Salles G et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99(3), 754–758 (2002).
    • 5 Weng W-K, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21(21), 3940–3947 (2003).
    • 6 Musolino A, Naldi N, Bortesi B et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu–positive metastatic breast cancer. J. Clin. Oncol. 26(11), 1789–1796 (2008).
    • 7 Zhang W, Gordon M, Schultheis AM et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor-expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J. Clin. Oncol. 25(24), 3712–3718 (2007).
    • 8 Cheung N-KV, Sowers R, Vickers AJ, Cheung IY, Kushner BH, Gorlick R. FCGR2A polymorphism is correlated with clinical outcome after immunotherapy of neuroblastoma with anti-GD2 antibody and granulocyte macrophage colony-stimulating factor. J. Clin. Oncol. 24(18), 2885–2890 (2006).
    • 9 Farag SS, Flinn IW, Modali R, Lehman TA, Young D, Byrd JC. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 103(4), 1472–1474 (2004).
    • 10 Hurvitz SA, Betting DJ, Stern HM et al. Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin. Cancer Res. 18(12), 3478–3486 (2012).
    • 11 Paez D, Pare L, Espinosa I et al. Immunoglobulin G fragment C receptor polymorphisms and KRAS mutations: are they useful biomarkers of clinical outcome in advanced colorectal cancer treated with anti-EGFR-based therapy? Cancer Sci. 101(9), 2048–2053 (2010).
    • 12 Delgado DC, Hank JA, Kolesar J et al. Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14. 18-IL2 immunotherapy. Cancer Res. 70(23), 9554–9561 (2010).
    • 13 Tarek N, Le Luduec J-B, Gallagher MM et al. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J. Clin. Invest. 122(9), 3260 (2012).
    • 14 Taylor RP, Lindorfer MA. The role of complement in mAb-based therapies of cancer. Methods 65(1), 18–27 (2014).
    • 15 Meyer S, Leusen JH, Boross P. Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer. MAbs 6(5), 1133–1144 (2014).
    • 16 Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 19(56), 6550–6565 (2000).
    • 17 Honeychurch J, Alduaij W, Azizyan M et al. Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway. Blood 119(15), 3523–3533 (2012).
    • 18 Doronin Ii, Vishnyakova PA, Kholodenko IV et al. Ganglioside GD2 in reception and transduction of cell death signal in tumor cells. BMC Cancer 14 295 (2014).
    • 19 Mossner E, Brunker P, Moser S et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115(22), 4393–4402 (2010).
    • 20 Deans JP, Li H, Polyak MJ. CD20-mediated apoptosis: signalling through lipid rafts. Immunology 107(2), 176–182 (2002).
    • 21 Brodeur GM, Maris JM, Yamashiro DJ, Hogarty MD, White PS. Biology and genetics of human neuroblastomas. J. Pediat. Hematol. Onc. 19(2), 93–101 (1997).
    • 22 Seeger RC, Brodeur GM, Sather H et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. New. Engl. J. Med. 313(18), 1111–1116 (1985).
    • 23 Shimada H, Stram DO, Chatten J et al. Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis. J. Natl. Cancer I. 87(19), 1470–1476 (1995).
    • 24 Matthay KK, Villablanca JG, Seeger RC et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N. Engl. J. Med. 341(16), 1165–1173 (1999).
    • 25 Schulz G, Cheresh DA, Varki NM, Yu A, Staffileno LK, Reisfeld RA. Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res. 44(12 Part 1), 5914–5920 (1984).
    • 26 Yoshida S, Fukumoto S, Kawaguchi H, Sato S, Ueda R, Furukawa K. Ganglioside GD2 in small cell lung cancer cell lines enhancement of cell proliferation and mediation of apoptosis. Cancer Res. 61(10), 4244–4252 (2001).
    • 27 Shibuya H, Hamamura K, Hotta H et al. Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3. Cancer Sci. 103(9), 1656–1664 (2012).
    • 28 Saarinen UM, Coccia PF, Gerson SL, Pelley R, Cheung N-KV. Eradication of neuroblastoma cells in vitro by monoclonal antibody and human complement: method for purging autologous bone marrow. Cancer Res. 45(11 Part 2), 5969–5975 (1985).
    • 29 Kushner BH, Cheung N-KV. Clinically effective monoclonal antibody 3F8 mediates nonoxidative lysis of human neuroectodermal tumor cells by polymorphonuclear leukocytes. Cancer Res. 51(18), 4865–4870 (1991).
    • 30 Munn D, Garnick M, Cheung N. Effects of parenteral recombinant human macrophage colony-stimulating factor on monocyte number, phenotype, and antitumor cytotoxicity in nonhuman primates. Blood 75(10), 2042–2048 (1990).
    • 31 Munn DH, Cheung N. Phagocytosis of tumor cells by human monocytes cultured in recombinant macrophage colony-stimulating factor. J. Exp. Med. 172(1), 231–237 (1990).
    • 32 Honsik CJ, Jung G, Reisfeld RA. Lymphokine-activated killer cells targeted by monoclonal antibodies to the disialogangliosides GD2 and GD3 specifically lyse human tumor cells of neuroectodermal origin. Proc. Natl Acad. Sci. USA 83(20), 7893–7897 (1986).
    • 33 Harel W, Shau H, Hadley CG et al. Increased lysis of melanoma by in vivo-elicited human lymphokine-activated killer cells after addition of antiganglioside antibodies in vitro. Cancer Res. 50(19), 6311–6315 (1990).
    • 34 Cheung N-KV, Lazarus H, Miraldi FD et al. Ganglioside GD2 specific monoclonal antibody 3F8: a Phase I study in patients with neuroblastoma and malignant melanoma. J. Clin. Oncol. 5(9), 1430–1440 (1987).
    • 35 Cheung N, Kushner BH, Yeh S, Larson SM. 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: a Phase II study. Int. J. Oncol. 12(6), 1299–1605 (1998).
    • 36 Cheung N, Kushner BH, Cheung IY et al. Anti-G (D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J. Clin. Oncol. 16(9), 3053–3060 (1998).
    • 37 Hank JA, Robinson RR, Surfus J et al. Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2. Cancer Res. 50(17), 5234–5239 (1990).
    • 38 Munn DH, Cheung N-KV. Interleukin-2 enhancement of monoclonal antibody-mediated cellular cytotoxicity against human melanoma. Cancer Res. 47(24 Part 1), 6600–6605 (1987).
    • 39 Kushner BH, Cheung N. GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. Blood 73(7), 1936–1941 (1989).
    • 40 Kushner BH, Kramer K, Cheung N-KV. Phase II trial of the anti-GD2 monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma. J. Clin. Oncol. 19(22), 4189–4194 (2001).
    • 41 Cheung N-KV, Cheung IY, Kushner BH et al. Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J. Clin. Oncol. 30, 3264–3270 (2012).
    • 42 Cheung NKV, Cheung IY, Kramer K et al. Key role for myeloid cells: Phase II results of anti-GD2 antibody 3F8 plus granulocyte-macrophage colony-stimulating factor for chemoresistant osteomedullary neuroblastoma. Int. J. Cancer 135(9), 2199–2205 (2014).
    • 43 Dobrenkov K, Cheung N-KV. GD2-targeted immunotherapy and radioimmunotherapy. Semin. Oncol. 41(5), 589–612 (2014).
    • 44 Thurin J, Thurin M, Kimoto Y et al. Monoclonal antibody-defined correlations in melanoma between levels of GD2 and GD3 antigens and antibody-mediated cytotoxicity. Cancer Res. 47(5), 1229–1233 (1987).
    • 45 Iliopoulos D, Ernst C, Steplewski Z et al. Inhibition of metastases of a human melanoma xenograft by monoclonal antibody to the GD2/GD3 gangliosides. J. Natl Cancer Inst. 81(6), 440–444 (1989).
    • 46 Mujoo K, Kipps TJ, Yang HM et al. Functional properties and effect on growth suppression of human neuroblastoma tumors by isotype switch variants of monoclonal antiganglioside GD2 antibody 14.18. Cancer Res. 49(11), 2857–2861 (1989).
    • 47 Handgretinger R, Baader P, Dopfer R et al. A Phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14. G2a. Cancer Immunol. Immun. 35(3), 199–204 (1992).
    • 48 Saleh MN, Khazaeli M, Wheeler RH et al. Phase I trial of the murine monoclonal anti-GD2 antibody 14G2a in metastatic melanoma. Cancer Res. 52(16), 4342–4347 (1992).
    • 49 Murray JL, Cunningham JE, Brewer H et al. Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors. J. Clin. Oncol. 12(1), 184–193 (1994).
    • 50 Frost JD, Hank JA, Reaman GH et al. A Phase I/IB trial of murine monoclonal anti-GD2 antibody 14. G2a plus interleukin-2 in children with refractory neuroblastoma. Cancer 80(2), 317–333 (1997).
    • 51 Gillies SD, Lo K-M, Wesolowski J. High-level expression of chimeric antibodies using adapted cDNA variable region cassettes. J. Immunol. Methods 125(1), 191–202 (1989).
    • 52 Mueller BM, Romerdahl CA, Gillies SD, Reisfeld RA. Enhancement of antibody-dependent cytotoxicity with a chimeric anti-GD2 antibody. J. Immunol. 144(4), 1382–1386 (1990).
    • 53 Barker E, Mueller BM, Handgretinger R, Herter M, Alice LY, Reisfeld RA. Effect of a chimeric anti-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells. Cancer Res. 51(1), 144–149 (1991).
    • 54 Albertini MR, Gan J, Jaeger P et al. Systemic interleukin-2 modulates the anti-idiotypic response to chimeric anti-GD2 antibody in patients with melanoma. J. Immunother. 19(4), 278–295 (1996).
    • 55 Uttenreuther-Fischer M, Huang C, Yu A. Pharmacokinetics of human-mouse chimeric anti-GD2 mAb ch14. 18 in a Phase I trial in neuroblastoma patients. Cancer Immunol. Immun. 41(6), 331–338 (1995).
    • 56 Yu A, Uttenreuther-Fischer MM, Huang C-S et al. Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14. 18 in patients with refractory neuroblastoma and osteosarcoma. J. Clin. Oncol. 16(6), 2169–2180 (1998).
    • 57 Handgretinger R, Anderson K, Lang P et al. A Phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14. 18 in patients with neuroblastoma. Eur. J. Cancer 31(2), 261–267 (1995).
    • 58 Simon T, Hero B, Faldum A et al. Consolidation treatment with chimeric anti-GD2-antibody ch14. 18 in children older than 1 year with metastatic neuroblastoma. J. Clin. Oncol. 22(17), 3549–3557 (2004).
    • 59 Simon T, Hero B, Faldum A et al. Infants with stage 4 neuroblastoma: the impact of the chimeric anti-GD2-antibody ch14. 18 consolidation therapy. Klin. Padiatr. 217(3), 147–152 (2004).
    • 60 Simon T, Hero B, Faldum A et al. Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14. 18 or oral metronomic chemotherapy. BMC Cancer 11(1), 21 (2011).
    • 61 Ozkaynak MF, Sondel PM, Krailo MD et al. Phase I study of chimeric human/murine anti–ganglioside GD2 monoclonal antibody (ch14. 18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a children’s cancer group study. J. Clin. Oncol. 18(24), 4077–4085 (2000).
    • 62 Desai AV, Fox E, Smith LM, Lim AP, Maris JM, Balis FM. Pharmacokinetics of the chimeric anti-GD2 antibody, ch14. 18, in children with high-risk neuroblastoma. Cancer Chemoth. Pharm. 74(5), 1047–1055 (2014).
    • 63 Albertini MR, Hank JA, Schiller JH et al. Phase IB trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients. Clin. Cancer Res. 3(8), 1277–1288 (1997).
    • 64 Choi BS, Sondel PM, Hank JA et al. Phase I trial of combined treatment with ch14. 18 and R24 monoclonal antibodies and interleukin-2 for patients with melanoma or sarcoma. Cancer Immunol. Immun. 55(7), 761–774 (2006).
    • 65 Gilman AL, Ozkaynak MF, Matthay KK et al. Phase I study of ch14. 18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children’s Oncology Group. J. Clin. Oncol. 27(1), 85–91 (2009).
    • 66 Yu AL, Gilman AL, Ozkaynak MF et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363(14), 1324–1334 (2010).
    • 67 Ladenstein R, Pötschger U, Siabalis D et al. Dose finding study for the use of subcutaneous recombinant interleukin-2 to augment natural killer cell numbers in an outpatient setting for stage 4 neuroblastoma after megatherapy and autologous stem-cell reinfusion. J. Clin. Oncol. 29(4), 441–448 (2010).
    • 68 Ladenstein RL, Poetschger U, Luksch R et al. Immunotherapy (IT) with ch14. 18/CHO for high-risk neuroblastoma: first results from the randomised HR-NBL1/SIOPEN trial. J. Clin. Oncol. 32(Suppl. 5s), Abstract 10026 (2014).
    • 69 Lode HN, Valteau-Couanet D, Garaventa A et al. Long-term infusion of anti-GD2 antibody ch14. 18/CHO in combination with interleukin-2 (IL2) activity and efficacy in high-risk relapsed/refractory neuroblastoma patients. J. Clin. Oncol. 33(Suppl.), Abstract TPS10080 (2015).
    • 70 Park JR, Bagatell R, London WB et al. Children’s Oncology Group’s 2013 blueprint for research: neuroblastoma. Pediatr. Blood Cancer 60(6), 985–993 (2013).
    • 71 Saleh MN, Khazaeli M, Wheeler RH et al. Phase I trial of the chimeric anti-GD2 monoclonal antibody ch14. 18 in patients with malignant melanoma. Hum. ABS 3(1), 19–24 (1992).
    • 72 Brüggemann M, Winter G, Waldmann H, Neuberger M. The immunogenicity of chimeric antibodies. J. Exp. Med. 170(6), 2153–2157 (1989).
    • 73 Sorkin LS, Otto M, Baldwin WM et al. Anti-GD 2 with an FC point mutation reduces complement fixation and decreases antibody-induced allodynia. Pain 149(1), 135–142 (2010).
    • 74 Thommesen JE, Michaelsen TE, Løset GÅ, Sandlie I, Brekke OH. Lysine 322 in the human IgG3 C H 2 domain is crucial for antibody dependent complement activation. Mol. Immunol. 37(16), 995–1004 (2000).
    • 75 Ito A, Ishida T, Yano H et al. Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rγnull mouse model. Cancer Immunol. Immun. 58(8), 1195–1206 (2009).
    • 76 Alderson KL, Luangrath M, Elsenheimer MM et al. Enhancement of the anti-melanoma response of Hu14. 18K322A by αCD40+ CpG. Cancer Immunol. Immun. 62(4), 665–675 (2013).
    • 77 Vāvere AL, Butch ER, Dearling JL et al. 64Cu-p-NH2-Bn-DOTA-hu14. 18K322A, a PET radiotracer targeting neuroblastoma and melanoma. J. Nucl. Med. 53(11), 1772–1778 (2012).
    • 78 Anghelescu DL, Goldberg JL, Faughnan LG et al. Comparison of pain outcomes between two anti-GD2 antibodies in patients with neuroblastoma. Pediatr. Blood Cancer 62(2), 224–228 (2015).
    • 79 Navid F, Sondel PM, Barfield R et al. Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14. 18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma. J. Clin. Oncol. 32(14), 1445–1452 (2014).
    • 80 Cheung N-KV, Guo H, Hu J, Tassev DV, Cheung IY. Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo. Oncoimmunology 1(4), 477–486 (2012).
    • 81 Ye JN, Cheung NKV. A novel O-acetylated ganglioside detected by anti-GD2 monoclonal antibodies. Int. J. Cancer 50(2), 197–201 (1992).
    • 82 Alvarez-Rueda N, Desselle A, Cochonneau D et al. A monoclonal antibody to O-acetyl-GD2 ganglioside and not to GD2 shows potent antitumor activity without peripheral nervous system cross-reactivity. PLoS One 6(9), e25220 (2011).
    • 83 Cerato E, Birkle S, Portoukalian J, Mezazigh A, Chatal J-F, Aubry J. Variable region gene segments of nine monoclonal antibodies specific to disialogangliosides (GD2, GD3) and their O-acetylated derivatives. Hybridoma 16(4), 307–316 (1997).
    • 84 Terme M, Dorvillius M, Cochonneau D et al. Chimeric antibody c. 8B6 to O-acetyl-GD2 mediates the same efficient anti-neuroblastoma effects as therapeutic ch14. 18 antibody to GD2 without antibody induced allodynia. PLoS One 9(2), e87210 (2014).
    • 85 Sondel PM, Gillies SD. Immunocytokines for cancer immunotherapy. In: Handbook Of Cancer Vaccines. Morse MA, Clay TM, Lyerly HK (Eds). Humana Press, NYUSA 341–358 (2004).
    • 86 Gillies SD, Reilly EB, Lo K-M, Reisfeld RA. Antibody-targeted interleukin 2 stimulates T-cell killing of autologous tumor cells. Proc. Natl Acad. Sci. USA 89(4), 1428–1432 (1992).
    • 87 Sabzevari H, Gillies SD, Mueller BM, Pancook JD, Reisfeld RA. A recombinant antibody–interleukin 2 fusion protein suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice. Proc. Natl Acad. Sci. USA 91(20), 9626–9630 (1994).
    • 88 Hank JA, Surfus JE, Gan J et al. Activation of human effector cells by a tumor reactive recombinant anti-ganglioside GD2 interleukin-2 fusion protein (ch14. 18-IL2). Clin. Cancer Res. 2(12), 1951–1959 (1996).
    • 89 Kendra K, Gan J, Ricci M et al. Pharmacokinetics and stability of the ch14.18–interleukin-2 fusion protein in mice. Cancer Immunol. Immun. 48(5), 219–229 (1999).
    • 90 Lode HN, Xiang R, Dreier T, Varki NM, Gillies SD, Reisfeld RA. Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy. Blood 91(5), 1706–1715 (1998).
    • 91 Lode HN, Xiang R, Dolman CS, Reisfeld RA, Varki NM, Gillies SD. Targeted interleukin-2 therapy for spontaneous neuroblastoma metastases to bone marrow. J. Natl Cancer Inst. 89(21), 1586–1594 (1997).
    • 92 Niculescu-Duvaz I. Technology evaluation: EMD-273063, EMD Lexigen. Curr. Opin. Mol. Ther. 6(5), 559–566 (2004).
    • 93 Lode HN, Xiang R, Pertl U et al. Melanoma immunotherapy by targeted IL-2 depends on CD4+ T-cell help mediated by CD40/CD40L interaction. J. Clin. Invest. 105(11), 1623 (2000).
    • 94 Neal ZC, Yang JC, Rakhmilevich AL et al. Enhanced activity of hu14. 18-IL2 immunocytokine against murine NXS2 neuroblastoma when combined with interleukin 2 therapy. Clin. Cancer Res. 10(14), 4839–4847 (2004).
    • 95 Neal ZC, Imboden M, Rakhmilevich AL et al. NXS2 murine neuroblastomas express increased levels of MHC class I antigens upon recurrence following NK-dependent immunotherapy. Cancer Immunol. Immun. 53(1), 41–52 (2004).
    • 96 Osenga KL, Hank JA, Albertini MR et al. A Phase I clinical trial of the hu14. 18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children’s Oncology Group. Clin. Cancer Res. 12(6), 1750–1759 (2006).
    • 97 King DM, Albertini MR, Schalch H et al. Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. J. Clin. Oncol. 22(22), 4463–4473 (2004).
    • 98 Ribas A, Kirkwood JM, Atkins MB et al. Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14. 18-IL2) in patients with metastatic malignant melanoma. J. Transl. Med. 7, 68 (2009).
    • 99 Albertini MR, Hank JA, Gadbaw B et al. Phase II trial of hu14. 18-IL2 for patients with metastatic melanoma. Cancer Immunol. Immun. 61(12), 2261–2271 (2012).
    • 100 Shusterman S, London WB, Gillies SD 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. 28(33), 4969–4975 (2010).
    • 101 Gillies SD. A new platform for constructing antibody-cytokine fusion proteins (immunocytokines) with improved biological properties and adaptable cytokine activity. Protein Eng. Des. Sel. 26(10), 561–569 (2013).
    • 102 Fehniger TA, Cooper MA, Caligiuri MA. Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth F. R. 13(2), 169–183 (2002).
    • 103 Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in cancer. Trend. Pharmacol. Sci. 33(1), 35–41 (2012).
    • 104 Vincent M, Bessard A, Cochonneau D et al. Tumor targeting of the IL-15 superagonist RLI by an anti-GD2 antibody strongly enhances its antitumor potency. Int. J. Cancer 133(3), 757–765 (2013).
    • 105 Vincent M, Quéméner A, Jacques Y. Antitumor activity of an immunocytokine composed of an anti-GD2 antibody and the IL-15 superagonist RLI. Oncoimmunology 2(11), e26441 (2013).
    • 106 Pastan I, Hassan R, Fitzgerald DJ, Kreitman RJ. Immunotoxin treatment of cancer. Annu. Rev. Med. 58, 221–237 (2007).
    • 107 Wargalla UC, Reisfeld RA. Rate of internalization of an immunotoxin correlates with cytotoxic activity against human tumor cells. Proc. Natl Acad. Sci. USA 86(13), 5146–5150 (1989).
    • 108 Gottstein C, Schön G, Tawadros S et al. Antidisialoganglioside ricin A-chain immunotoxins show potent antitumor effects in vitro and in a disseminated human neuroblastoma severe combined immunodeficiency mouse model. Cancer Res. 54(23), 6186–6193 (1994).
    • 109 Manzke O, Russello O, Leenen C, Diehl V, Bohlen H, Berthold F. Immunotherapeutic strategies in neuroblastoma: antitumoral activity of deglycosylated ricin A conjugated anti-GD2 antibodies and anti-CD3xanti-GD2 bispecific antibodies. Med. Pediatr. Oncol. 36(1), 185–189 (2001).
    • 110 Mujoo K, Reisfeld RA, Cheung L, Rosenblum MG. A potent and specific immunotoxin for tumor cells expressing disialoganglioside GD2. Cancer Immunol. Immun. 34(3), 198–204 (1991).
    • 111 Thomas PB, Delatte SJ, Sutphin A, Frankel AE, Tagge EP. Effective targeted cytotoxicity of neuroblastoma cells. J. Pediatr. Surg. 37(3), 539–544 (2002).
    • 112 Tur MK, Sasse S, Stocker M et al. An anti-GD2 single chain Fv selected by phage display and fused to Pseudomonas exotoxin A develops specific cytotoxic activity against neuroblastoma derived cell lines. Int. J. Mol. Med. 8(5), 579–584 (2001).
    • 113 Larson SM, Carrasquillo JA, Cheung N-KV, Press OW. Radioimmunotherapy of human tumours. Nat. Rev. Cancer 15(6), 347–360 (2015).
    • 114 Yeh S, Larson SM, Burch L et al. Radioimmunodetection of neuroblastoma with iodine-131–3F8: correlation with biopsy, iodine-131-metaiodobenzylguanidine and standard diagnostic modalities. J. Nucl. Med. 32(5), 769–776 (1991).
    • 115 Reuland P, Geiger L, Thelen MH et al. Follow-up in neuroblastoma: comparison of metaiodobenzylguanidine and a chimeric anti-GD2 antibody for detection of tumor relapse and therapy response. J. Pediat. Hematol. Oncol. 23(7), 437–442 (2001).
    • 116 Cheung N-KV, Landmeier B, Neely J et al. Complete tumor ablation with iodine 131-radiolabeled disialoganglioside GD2-specific monoclonal antibody against human neuroblastoma xenografted in nude mice. J. Natl Cancer Inst 77(3), 739–745 (1986).
    • 117 Kramer K, Kushner BH, Modak S et al. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J. Neurooncol. 97(3), 409–418 (2010).
    • 118 Cheung N-KV, Modak S, Lin Y et al. Single-chain Fv-streptavidin substantially improved therapeutic index in multistep targeting directed at disialoganglioside GD2. J. Nucl. Med. 45(5), 867–877 (2004).
    • 119 Lode HN, Reisfeld RA, Handgretinger R, Nicolaou KC, Gaedicke G, Wrasidlo W. Targeted therapy with a novel enediyene antibiotic calicheamicin ϑI1 effectively suppresses growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma. Cancer Res. 58(14), 2925–2928 (1998).
    • 120 Pastorino F, Brignole C, Loi M et al. Nanocarrier-mediated targeting of tumor and tumor vascular cells improves uptake and penetration of drugs into neuroblastoma. Front. Oncol. 3, 190 (2013).
    • 121 Pastorino F, Brignole C, Marimpietri D et al. Targeted liposomal c-myc antisense oligodeoxynucleotides induce apoptosis and inhibit tumor growth and metastases in human melanoma models. Clin. Cancer Res. 9(12), 4595–4605 (2003).
    • 122 Pastorino F, Brignole C, Marimpietri D et al. Doxorubicin-loaded Fab′ fragments of anti-disialoganglioside immunoliposomes selectively inhibit the growth and dissemination of human neuroblastoma in nude mice. Cancer Res. 63(1), 86–92 (2003).
    • 123 Brignole C, Pastorino F, Marimpietri D et al. Immune cell–mediated antitumor activities of GD2-targeted liposomal c-myb antisense oligonucleotides containing CpG motifs. J. Natl Cancer Inst. 96(15), 1171–1180 (2004).
    • 124 Raffaghello L, Pagnan G, Pastorino F et al. In vitro and in vivo antitumor activity of liposomal Fenretinide targeted to human neuroblastoma. Int. J. Cancer 104(5), 559–567 (2003).
    • 125 Tivnan A, Orr WS, Gubala V et al. Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles. PLoS One 7(5), e38129 (2012).
    • 126 Peng C-A, Wang C-H. Anti-neuroblastoma activity of gold nanorods bound with GD2 monoclonal antibody under near-infrared laser irradiation. Cancers 3(1), 227–240 (2011).
    • 127 Wang C-H, Huang Y-J, Chang C-W, Hsu W-M, Peng C-A. In vitro photothermal destruction of neuroblastoma cells using carbon nanotubes conjugated with GD2 monoclonal antibody. Nanotechnology 20(31), 315101 (2009).
    • 128 Xu Y, Baiu DC, Sherwood JA et al. Linker-free conjugation and specific cell targeting of antibody functionalized iron-oxide nanoparticles. J. Mater. Chem. B 2(37), 6198–6206 (2014).
    • 129 Thakur A, Lum LG. Cancer therapy with bispecific antibodies: clinical experience. Curr. Opin. Mol. Ther. 12(3), 340 (2010).
    • 130 Suzuki M, Curran KJ, Cheung NKV. Chimeric antigen receptors and bispecific antibodies to retarget T cells in pediatric oncology. Pediatr. Blood Cancer 62(8), 1326–1336 (2015).
    • 131 Xu H, Cheng M, Guo H, Chen Y, Huse M, Cheung N-KV. Retargeting T cells to GD2 pentasaccharide on human tumors using bispecific humanized antibody. Cancer Immunol. Res. 3(3), 266–277 (2014).
    • 132 Yankelevich M, Kondadasula SV, Thakur A, Buck S, Cheung NKV, Lum LG. Anti-CD3× anti-GD2 bispecific antibody redirects T-cell cytolytic activity to neuroblastoma targets. Pediatr. Blood Cancer 59(7), 1198–1205 (2012).
    • 133 Deppisch N, Ruf P, Eissler N et al. Efficacy and tolerability of a GD2-directed trifunctional bispecific antibody in a preclinical model: subcutaneous administration is superior to intravenous delivery. Mol. Cancer Ther. 14(8), 1877–1883 (2015).
    • 134 Cheng M, Ahmed M, Xu H, Cheung NKV. Structural design of disialoganglioside GD2 and CD3-bispecific antibodies to redirect T cells for tumor therapy. Int. J. Cancer 136(2), 476–486 (2015).
    • 135 Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25 years in the making. Blood Rev. doi: 10.1016/j.blre.2015.10.003 (2015) (Epub ahead of print).
    • 136 Louis CU, Savoldo B, Dotti G et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118(23), 6050–6056 (2011).
    • 137 Pule MA, Savoldo B, Myers GD et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14(11), 1264–1270 (2008).
    • 138 Hank JA, Gan J, Ryu H et al. Immunogenicity of the hu14. 18-IL2 immunocytokine molecule in adults with melanoma and children with neuroblastoma. Clin. Cancer Res. 15(18), 5923–5930 (2009).
    • 139 Siebert N, Seidel D, Eger C, Juttner M, Lode HN. Functional bioassays for immune monitoring of high-risk neuroblastoma patients treated with ch14.18/CHO anti-GD2 antibody. PLoS One 9(9), e107692 (2014).
    • 140 Mirick G, Bradt B, Denardo S, Denardo G. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words. Q. J. Nucl. Med. Mol. Imaging 48(4), 251 (2004).
    • 141 Kieber-Emmons T, Monzavi-Karbassi B, Pashov A, Saha S, Murali R, Kohler H. The promise of the anti-idiotype concept. Front. Oncol. 2, 196 (2012).
    • 142 Cheung N-KV, Guo H-F, Heller G, Cheung IY. Induction of Ab3 and Ab3′ antibody was associated with long-term survival after anti-GD2 antibody therapy of stage 4 neuroblastoma. Clin. Cancer Res. 6(7), 2653–2660 (2000).
    • 143 Sen G, Chakraborty M, Foon KA, Reisfeld RA, Bhattacharya-Chatterjee M. Preclinical evaluation in nonhuman primates of murine monoclonal anti-idiotype antibody that mimics the disialoganglioside GD2. Clin. Cancer Res. 3(11), 1969–1976 (1997).
    • 144 Foon KA, Lutzky J, Baral RN et al. Clinical and immune responses in advanced melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2. J. Clin. Oncol. 18(2), 376–376 (2000).
    • 145 Cacciavillano W, Sampor C, Venier C et al. A phase I study of the anti-idiotype vaccine racotumomab in neuroblastoma and other pediatric refractory malignancies. Pediatr. Blood Cancer 62(12), 2120–2124 (2015).
    • 146 Johnson EE, Lum HD, Rakhmilevich AL et al. Intratumoral immunocytokine treatment results in enhanced antitumor effects. Cancer Immunol. Immun. 57(12), 1891–1902 (2008).
    • 147 Yang RK, Kalogriopoulos NA, Rakhmilevich AL et al. Intratumoral hu14. 18–IL-2 (IC) induces local and systemic antitumor effects that involve both activated T and NK Cells as well as enhanced IC retention. J. Immunol. 189(5), 2656–2664 (2012).
    • 148 Yang RK, Kalogriopoulos NA, Rakhmilevich AL et al. Intratumoral treatment of smaller mouse neuroblastoma tumors with a recombinant protein consisting of IL-2 linked to the hu14. 18 antibody increases intratumoral CD8+ T and NK cells and improves survival. Cancer Immunol. Immun. 62(8), 1303–1313 (2013).
    • 149 Morris ZS, Guy EI, Francis DM et al. Immunocytokine augments local and abscopal response and animal survival when added to radiation and CTLA-4 checkpoint inhibition in a murine melanoma model. J. Immunother. Cancer 3(Suppl. 2), P308 (2015).
    • 150 Morris Z, Francis D, Gressett M et al. Combining local radiation and tumor-specific antibody or immunocytokine to elicit in situ tumor vaccination. Cancer Res. doi: 10.1158/0008-5472.CAN-15-2644 (2016) (Epub ahead of print).
    • 151 Ribas A. Releasing the brakes on cancer immunotherapy. N. Engl. J. Med. 373(16), 1490–1492 (2015).
    • 152 Brahmer JR, Drake CG, Wollner I et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28(19), 3167–3175 (2010).
    • 153 Khoja L, Butler MO, Kang SP, Ebbinghaus S, Joshua AM. Pembrolizumab. J. Immunother. Cancer 3(1), 1–13 (2015).
    • 154 Merchant M, Wright M, Baird K et al. Phase 1 clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clin. Cancer Res. 22(6), 1364–1370 (2015).
    • 155 Boes M, Meyer-Wentrup F. TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells. Cancer Lett. 361(1), 49–56 (2015).
    • 156 Dondero A, Pastorino F, Chiesa MD et al. PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance. OncoImmunology 5(1), e1064578 (2016).
    • 157 Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 16(4), 399–403 (2010).
    • 158 Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342(6165), 1432–1433 (2013).
    • 159 Handgretinger R, Anderson K, Lang P et al. A Phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14. 18 in patients with neuroblastoma. Eur. J. Cancer 31(2), 261–267 (1995).
    • 160 Kramer K, Humm JL, Souweidane MM et al. Phase I study of targeted radioimmunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8. J. Clin. Oncol. 25(34), 5465–5470 (2007).
    • 161 Pule MA, Savoldo B, Myers GD et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14(11), 1264–1270 (2008).
    • 162 Foon KA, Lutzky J, Baral RN et al. Clinical and immune responses in advanced melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2. J. Clin. Oncol. 18(2), 376–384 (2000).