Immunocytokines (ICs) are a class of molecules created by linking tumor-reactive monoclonal antibodies to cytokines that are able to activate immune cells. Tumor selective localization is provided by the ability of the mAb component to bind to molecules found on the tumor cell surface or molecules found selectively in the tumor microenvronment. In this way the cytokine component of the immunocytokine is selectively localized to sites of tumor and can activate immune cells with appropriate receptors for the cytokine. Immunocytokines have been made and tested by us, and others, using a variety of tumor-reactive mAbs linked to distinct cytokines. To date, the majority of clinical progress has been made with ICs that have linked human interleukin-2 (IL2) to a select number of tumor reactive mAbs that had already been in prior clinical testing as non-modified mAbs. Here we briefly review the background for the creation of ICs, summarize current clinical progress, emphasize mechanisms of action for ICs that are distinct from those of their constituent components, and present some directions for future development and testing.
References
[1]
Horowitz, M.M.; Gale, R.P.; Sondel, P.M.; Goldman, J.M.; Kerse, J.; Kolb, H.J.; Rimm, A.A.; Ringden, O.; Rozman, C.; Speck, B. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990, 75, 555–562.
[2]
Ferris, R.L.; Jaffee, E.M.; Ferrone, S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: Clinical response, cellular immunity, and immunoescape. J. Clin. Oncol. 2010, 28, 4390–4399, doi:10.1200/JCO.2009.27.6360.
[3]
Krege, S.; Giani, G.; Meyer, R.; Otto, T.; Rubben, H. A randomized multicenter trial of adjuvant therapy in superficial bladder cancer: Transurethral resection only versus transurethral resection plus mitomycin C versus transurethral resection plus bacillus Calmette-Guerin. Participating Clinics. J. Urol. 1996, 156, 962–966.
[4]
Rosenberg, S.A.; Yang, J.C.; Topalian, S.L.; Schwartzentruber, D.J.; Weber, J.S.; Parkinson, D.R.; Seipp, C.A.; Einhorn, J.H.; White, D.E. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994, 271, 907–913.
[5]
Kantoff, P.W.; Higano, C.S.; Shore, N.D.; Berger, E.R.; Small, E.J.; Penson, D.F.; Redfern, C.H.; Ferrari, A.C.; Dreicer, R.; Sims, R.B.; et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 2010, 363, 411–422.
[6]
Hodi, F.S.; O'Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. Engl. J. Med. 2010, 363, 711–723.
[7]
Fong, L.; Small, E.J. Anti-cytotoxic T-lymphocyte antigen-4 antibody: The first in an emerging class of immunomodulatory antibodies for cancer treatment. J. Clin. Oncol. 2008, 265, 275–283.
[8]
Yu, A.L.; Gilman, A.L.; Ozkaynak, M.F.; London, W.B.; Kreissman, S.; Chen, H.; Smith, M.; Anderson, B.; Villablanca, J.; Matthay, K.K.; et al. Chimeric Anti-GD2 Antibody with GM-CSF, IL2 and 13-cis Retinoic Acid for High-risk Neuroblastoma: A Children’s Oncology Group (COG) Phase 3 Study. N. Engl. J. Med. 2010, 335, 1324–1334.
[9]
Basham, T.Y.; Race, E.R.; Campbell, M.J.; Reid, T.R.; Levy, R.; Merigan, T.C. Synergistic antitumor activity with IFN and monoclonal anti-idiotype for murine B cell lymphoma. Mechanism of action. J. Immunol. 1988, 141, 2855–2860.
[10]
Primus, F.J.; Finch, M.D.; Wetzel, S.A.; Masci, A.M.; Schlom, J.; Kashmiri, S.V. Monoclonal antibody gene transfer. Implications for tumor-specific cell-mediated cytotoxicity. Ann. NY Acad. Sci. 1994, 716, 165–166.
[11]
Nimmerjahn, F.; Ravetch, J.V. Fcgamma receptors as regulators of immune responses. Nat. Rev. Immunol. 2008, 8, 34–47, doi:10.1038/nri2206.
[12]
Jefferis, R. Antibody therapeutics: Isotype and glycoform selection. Expert Opin. Biol. Th. 2007, 7, 1401–1413, doi:10.1517/14712598.7.9.1401.
[13]
Farag, S.S.; VanDeusen, J.B.; Fehniger, T.A.; Caligiuri, M.A. Biology and clinical impact of human natural killer cells. Int. J. Hematol. 2003, 78, 7–17, doi:10.1007/BF02983234.
[14]
Roda, J.M.; Parihar, R.; Magro, C.; Nuovo, G.J.; Tridandapani, S.; Carson, W.E., 3rd. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Cancer Res. 2006, 66, 517–526.
[15]
Orange, J.S. Formation and function of the lytic NK-cell immunological synapse. Nat. Rev. Immunol. 2008, 8, 713–725, doi:10.1038/nri2381.
[16]
Carlsten, M.; Malmberg, K.J.; Ljunggren, H.G. Natural killer cell-mediated lysis of freshly isolated human tumor cells. Int. J. Cancer 2009, 124, 757–762, doi:10.1002/ijc.24082.
Cartron, G.; Dacheux, L.; Salles, G.; Solal-Celigny, P.; Bardos, P.; Colombat, P.; Watier, H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002, 99, 754–758.
[19]
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. 2003, 21, 3940–3947, doi:10.1200/JCO.2003.05.013.
[20]
Treon, S.P.; Mitsiades, C.; Mitsiades, N.; Young, G.; Doss, D.; Schlossman, R.; Anderson, K.C. Tumor Cell Expression of CD59 Is Associated With Resistance to CD20 Serotherapy in Patients With B-Cell Malignancies. J. Immunother. 2001, 24, 263–271, doi:10.1097/00002371-200105000-00011.
[21]
Dzietczenia, J.; Wróbel, T.; Mazur, G.; Poreba, R.; Ja？wiec, B.; Kuliczkowski, K. Expression of complement regulatory proteins: CD46, CD55, and CD59 and response to rituximab in patients with CD20+ non-Hodgkin's lymphoma. Med. Oncol. 2010, 27, 743–746, doi:10.1007/s12032-009-9278-9.
[22]
Binyamin, L.; Alpaugh, R.K.; Hughes, T.L.; Lutz, C.T.; Campbell, K.S.; Weiner, L.M. Blocking NK cell inhibitory self-recognition promotes antibody-dependent cellular cytotoxicity in a model of anti-lymphoma therapy. J. Immunol. 2008, 180, 6392–6401.
[23]
Wang, S.Y.; Veeramani, S.; Racila, E.; Cagley, J.; Fritzinger, D.C.; Vogel, C.W.; St John, W.; Weiner, G.J. Depletion of the C3 component of complement enhances the ability of rituximab-coated target cells to activate human NK cells and improves the efficacy of monoclonal antibody therapy in an in vivo model. Blood 2009, 114, 5322–5330.
[24]
Shawver, L.K.; Slamon, D.; Ullrich, A. Smart drugs: Tyrosine kinase inhibitors in cancer therapy. Cancer Cell 2002, 1, 117–123, doi:10.1016/S1535-6108(02)00039-9.
[25]
Bibeau, F.; Lopez-Crapez, E.; Di Fiore, F.; Thezenas, S.; Ychou, M.; Blanchard, F.; Lamy, A.; Penault-Llorca, F.; Frébourg, T.; Michel, P.; et al. Impact of FcgRIIa-FcgRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J. Clin. Oncol. 2009, 27, 1122–1129.
[26]
Musolino, A.; Naldi, N.; Bortesi, B.; Pezzuolo, D.; Capelletti, M.; Missale, G.; Laccabue, D.; Zerbini, A.; Camisa, R.; Bisagni, G.; 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. 2008, 26, 1789–1796.
[27]
Shan, D.; Ledbetter, J.A.; Press, O.W. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 1998, 91, 1644–1652.
[28]
Cheung, N.K.; Sowers, R.; Vickers, A.J.; Cheung, I.Y.; Kushner, B.H.; 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. 2006, 24, 2885–2890.
[29]
Weng, W.K.; Czerwinski, D.; Levy, R. Humoral immune response and immunoglobulin G Fc receptor genotype are associated with better clinical outcome following idiotype vaccination in follicular lymphoma patients regardless of their response to induction chemotherapy. Blood 2007, 109, 951–953.
[30]
Wang, B.; Kokhaei, P.; Mellstedt, H.; Liljefors, M. FcγR polymorphisms and clinical outcome in colorectal cancer patients receiving passive or active antibody treatment. Int. J. Oncol. 2010, 37, 1599–1606.
[31]
Roda, J.M.; Joshi, T.; Butchar, J.P.; McAlees, J.W.; Lehman, A.; Tridandapani, S.; Carson, W.E., 3rd. The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Clin. Cancer Res. 2007, 13, 6419–6428.
[32]
Kloess, S.; Huenecke, S.; Piechulek, D.; Esser, R.; Koch, J.; Brehm, C.; Soerensen, J.; Gardlowski, T.; Brinkmann, A.; Bader, P.; et al. IL-2-activated haploidentical NK cells restore NKG2D-mediated NK-cell cytotoxicity in neuroblastoma patients by scavenging of plasma MICA. Eur. J. Immunol. 2010, 40, 3255–3267.
[33]
Hank, J.A.; Kohler, P.C.; Weil-Hillman, G.; Rosenthal, N.; Moore, K.H.; Storer, B.; Minkoff, D.; Bradshaw, J.; Bechhofer, R.; Sondel, P.M. In vivo induction of the lymphokine-activated killer phenomenon: Interleukin 2-dependent human non-major histocompatibility complex-restricted cytotoxicity generated in vivo during administration of human recombinant Interleukin 2. Cancer Res. 1988, 48, 1965–1971.
[34]
Hank, J.A.; Robinson, R.R.; Surfus, J.; Mueller, B.M.; Reisfeld, R.A.; Cheung, N.-K.; Sondel, P.M. Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant Interleukin-2. Cancer Res. 1990, 50, 5234–5239.
[35]
Sosman, J.A.; Hank, J.A.; Sondel, P.M. In vivo activation of lymphokine-activated killer activity with Interleukin-2: Prospects for combination therapies. Semin. Oncol. 1990, 17, 22–30.
[36]
Hank, J.A.; Albertini, M.R.; Schiller, J.; Sondel, P.M. Activation of multiple effector mechanisms to enhance tumor immunotherapy. J. Immunother. 1993, 14, 329–335, doi:10.1097/00002371-199311000-00013.
[37]
Mujoo, K.; Kipps, T.J.; Yang, H.M.; Cheresh, D.A.; Wargalla, U.; Sander, D.J.; Reisfeld, R.A. Functional properties and effect on growth suppression of human neuroblastoma tumors by isotype switch variants of monoclonal antiganglioside GD2 antibody 14.18. Cancer Res. 1989, 49, 2857–2861.
[38]
Kendra, K.; Malkovska, V.; Allen, M.; Guzman, J.; Albertini, M. In vivo binding and antitumor activity of Ch14.18. J. Immunother. 1999, 5, 23–430.
[39]
Neal, Z.C.; Yang, J.C.; Rakhmilevich, A.L.; Buhtoiarov, I.; Lum, H.E.; Imboden, M.; Hank, J.A.; Lode, H.N.; Reisfeld, R.A.; Gillies, S.D.; et al. Enhanced activity of hu14.18-IL2 immunocytokine against the murine NXS2 neuroblastoma when combined with IL2 therapy. Clin. Cancer Res. 2004, 10, 4839–4847.
[40]
Hank, J.; Surfus, J.; Gan, J.; Chew, T.-L.; Hong, R.; Tans, K.; Reisfeld, R.; Seeger, R.; Reynolds, C.P.; Bauer, M.; et al. Treatment of neuroblastoma patients with antiganglioside GD2 antibody plus Interleukin-2 induces antibody dependent cellular cytotoxicity against neuroblastoma detected in vitro. J. Immunother. 1994, 15, 29–37, doi:10.1097/00002371-199401000-00004.
[41]
Frost, J.D.; Ettinger, L.J.; Hank, J.A.; Cairo, M.S.; Reaman, G.H.; Blazar, B.R.; Frierdich, S.; Krailo, M.; Seeger, R.C.; Matthay, K.; et al. Phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus IL-2 in children with refractory neuroblastoma: A report of the Children’s Cancer Group. Cancer 1997, 80, 317–333, doi:10.1002/(SICI)1097-0142(19970715)80:2<317::AID-CNCR21>3.0.CO;2-W.
[42]
Albertini, M.R.; Hank, J.A.; Schiller, J.H.; Khorsand, M.; Borchert, A.A.; Gan, J.; Bechhofer, R.; Storer, B.; Reisfeld, R.A.; Sondel, P.M. Phase IB trial of chimeric anti-GD2 antibody plus interleukin-2 for melanoma patients. Clin. Cancer Res. 1997, 3, 1277–1288.
[43]
Gilman, A.L.; Ozkaynak, F.; Matthay, K.; Krailo, M.; Yu, A.; Gan, J.; Sternberg, A.; Hank, J.; Seeger, R.; Reaman, G.; et al. Phase I Study of ch14.18 with GM-CSF and IL-2 in Children with Neuroblastoma Following Autologous Bone Marrow Transplant or Stem Cell Rescue: A Report from the Children’s Oncology Group. J. Clin. Oncol. 2009, 27, 85–91.
[44]
Yu, A.L.; Batova, A.; Alvarado, C.; Rao, V.J.; Castleberry, R.P. Usefulness of a chimeric anti-GD2 (ch14.18) and GM-CSF for refractory neuroblastoma. Proc. Am. Assoc. Clin. Oncol. 1997, 6, 1846.
[45]
Kushner, B.H.; Kramer, K.; Cheung, N.K. Phase II trial of the anti-G(D2) monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma. J. Clin. Oncol. 2001, 19, 4189–4194.
[46]
Arndt, C.A.; Koshkina, N.V.; Inwards, C.Y.; Hawkins, D.S.; Krailo, M.D.; Villaluna, D.; Anderson, P.M.; Goorin, A.M.; Blakely, M.L.; Bernstein, M.; et al. Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: Effects on disease-free survival and immunomodulation. A report from the Children's Oncology Group. Clin. Cancer Res. 2010, 16, 4024–4030.
[47]
Simon, T.; Hero, B.; Faldum, A.; Handgretinger, R.; Schrappe, M.; Niethammer, D.; Berthold, F. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J. Clin. Oncol. 2004, 22, 3549–3557, doi:10.1200/JCO.2004.08.143.
[48]
Weil-Hillman, G.; Fisch, P.; Prieves, A.F.; Sosman, J.A.; Hank, J.A.; Sondel, P.M. Lymphokine-activated killer activity induced by in vivo interleukin-2 therapy: Predominant role for lymphocytes with increased expression of CD2 and Leul9 antigens but negative expression of CD16 antigens. Cancer Res. 1989, 49, 3680–3688.
[49]
Voss, S.D.; Robb, R.J.; Weil-Hillman, G.; Hank, J.A.; Sugamum, K.; Tsudo, M.; Sondel, P.M. Increased expression of the interleukin-2 (IL2) receptor beta chain (p70) on CD56+ natural killer cells after in vivo IL2 therapy: p70 expression does not alone predict the level of intermediate affinity IL2 binding. J. Exp. Med. 1990, 172, 1101–1114.
[50]
Sondel, P.M.; Kohler, P.C.; Hank, J.A.; Moore, K.H.; Rosenthal, N.; Sosman, J.; Bechhofer, R.; Storer, B. Clinical and immunological effects of recombinant interleukin-2 given by repetitive weekly cycles to subjects with cancer. Cancer Res. 1988, 48, 2561–2567.
[51]
Gillies, S.D.; Reilly, E.B.; Lo, K.-M.; Reisfeld, R.A. Antibody-targeted interleukin 2 stimulates the T-cell killing of autologous tumor cells. Proc. Natl. Acad. Sci. USA 1992, 89, 1428.
[52]
Hank, J.A.; Surfus, J.E.; Gan, J.; Jaeger, P.; Gillies, S.; Reisfeld, R.A.; Sondel, P.M. Activation of human effector cells by a tumor reactive recombinant anti-ganglioside GD2/interleukin-2 immunocytokine (ch14.18-IL2). Clin. Cancer Res. 1996, 2, 1951–1959.
[53]
Sabzevari, H.; Gillies, S.D.; Mueller, B.M.; Pancook, J.D.; Reisfeld, R.A. A recombinant antibody-interleukin 2 immunocytokine suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice. Proc. Natl. Acad. Sci. USA 1994, 91, 9626.
[54]
Becker, J.C.; Pancook, J.D.; Gillies, S.D.; Furukawa, K.; Reisfeld, R.A. T cell mediated eradiation of murine metastatic melanoma induced by targeted interleukin-2 therapy. J. Exp. Med. 1996, 183, 2361, doi:10.1084/jem.183.5.2361.
[55]
Becker, J.C.; Varki, N.; Gillies, S.D.; Furukawa, K.; Reisfeld, R.A. An antibody-interleukin-2 fusion protein overcomes tumor heterogeneity by induction of a cellular immune response. Proc. Natl. Acad. Sci. USA 1996, 93, 7826–7831.
[56]
Lode, H.N.; Xiang, R.; Varki, N.M.; Dolman, C.S.; Gillies, S.D.; Reisfeld, R.A. Targeted interleukin-2 therapy of spontaneous neuroblastoma to bone marrow. J. Natl. Cancer Inst. 1997, 89, 1586–1591, doi:10.1093/jnci/89.21.1586.
[57]
Lode, H.N.; Xiang, R.; Drier, T.; Varki, N.M.; Gillies, S.D.; Reisfeld, R.A. Natural killer cell mediated eradication of neuroblastoma metastases to bone marrow by targeted IL2 therapy. Blood 1998, 91, 1706–1715.
[58]
Neal, Z.C.; Imboden, M.; Rakhmilevich, A.L.; Kim, K.M.; Hank, J.A.; Surfus, J.; Dixon, J.R.; Lode, H.N.; Reisfeld, R.A.; Gillies, S.D. NXS2 murine neuroblastomas express increased levels of MHC class I antigens upon recurrence following NK-dependent immunotherapy. Cancer Immunol Immun. 2003, 53, 41–52.
[59]
King, D.M.; Albertini, M.R.; Schalch, H.; Hank, J.A.; Gan, J.; Surfus, J.; Mahvi, D.; Schiller, J.H.; Warner, T.; Kim, K.M.; et al. A Phase I Clinical Trial of the Immunocytokine EMD 273063 (hu14.18-IL2) in Patients with melanoma. J. Clin. Oncol. 2004, 22, 4463–4473.
[60]
Osenga, K.L.; Hank, J.A.; Albertini, M.R.; Gan, J.; Sternberg, A.G.; Eickhoff, J.; Seeger, R.C.; Matthay, K.K.; Reynolds, C.P.; Twist, C.; et al. A Phase I Clinical Trial of 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. 2005, 12, 1750–1759.
[61]
Shusterman, S.; London, W.B.; Gillies, S.D.; Hank, J.A.; Voss, S.; Seeger, R.C.; Reynolds, C.P.; Kimball, J.; Albertini, M.A.; Wagner, B.; Gan, J.; et al. Anti-tumor activity of hu14.18-IL2 in relapsed/refractory neuroblastoma patients: A Children’s Oncology Group (COG) phase II study. J. Clin. Oncol. 2010, 28, 4969–4975.
[62]
Joncker, N.T.; Shifrin, N.; Delebecque, F.; Raulet, D.H. Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J. Exp. Med. 2010, 207, 2065–2072, doi:10.1084/jem.20100570.
[63]
Elliott, J.M.; Wahle, J.A.; Yokoyama, W.M. MHC class I-deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I-sufficient environment. J. Exp. Med. 2010, 207, 2073–2079, doi:10.1084/jem.20100986.
Vivier, E.; Raulet, D.H.; Moretta, A.; Caligiuri, M.A.; Zitvogel, L.; Lanier, L.L.; Yokoyama, W.M.; Ugolini, S. Innate or adaptive immunity? The example of natural killer cells. Science 2011, 331, 44–49.
[67]
Anfossi, N.; André, P.; Guia, S.; Falk, C.S.; Roetynck, S.; Stewart, C.A.; Breso, V.; Frassati, C.; Reviron, D.; Middleton, D.; et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 2006, 25, 331–342, doi:10.1016/j.immuni.2006.06.013.
[68]
Yawata, M.; Yawata, N.; Draghi, M.; Partheniou, F.; Little, A.M.; Parham, P. MHC class I-specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response. Blood 2008, 112, 2369–2380, doi:10.1182/blood-2008-03-143727.
[69]
Sola, C.; André, P.; Lemmers, C.; Fuseri, N.; Bonnafous, C.; Bléry, M.; Wagtmann, N.R.; Romagné, F.; Vivier, E.; Ugolini, S. Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo. Proc. Natl. Acad. Sci. USA 2009, 106, 12879–12884.
[70]
Sola, C.; André, P.; Lemmers, C.; Fuseri, N.; Bonnafous, C.; Bléry, M.; Wagtmann, N.R.; Romagné, F.; Vivier, E.; Ugolini, S. Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo. Proc. Natl. Acad. Sci. USA 2009, 106, 12879–12884.
[71]
Pende, D.; Marcenaro, S.; Falco, M.; Martini, S.; Bernardo, M.E.; Montagna, D.; Romeo, E.; Cognet, C.; Martinetti, M.; Maccario, R.; et al. Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: Evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood 2009, 113, 3119–3129.
[72]
Moesta, A.K.; Norman, P.J.; Yawata, M.; Yawata, N.; Gleimer, M.; Parham, P. Synergistic Polymorphism at Two Positions Distal to the Ligand-Binding Site Makes KIR2DL2 a Stronger Receptor for HLA-C than KIR2DL3. J. Immol. 2008, 180, 3969–3979.
[73]
Stern, M.; Ruggeri, L.; Capanni, M.; Mancusi, A.; Velardi, A. Human leukocyte antigens A23, A24, and A32 but not A25 are ligands for KIR3DL1. Blood 2008, 112, 708–710.
[74]
Ruggeri, L.; Capanni, M.; Urbani, E.; Perruccio, K.; Shlomchik, W.D.; Tosti, A.; Posati, S.; Rogaia, D.; Frassoni, F.; Aversa, F.; et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002, 295, 2097–2100.
[75]
Ruggeri, L.; Mancusi, A.; Burchielli, E.; Capanni, M.; Carotti, A.; Aloisi, T.; Aversa, F.; Martelli, M.F.; Velardi, A. NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation. Blood Cells Mol. Dis. 2008, 40, 84–90, doi:10.1016/j.bcmd.2007.06.029.
[76]
Leung, W.; Iyengar, R.; Turner, V.; Lang, P.; Bader, P.; Conn, P.; Niethammer, D.; Handgretinger, R. Determinants of antileukemia effects of allogeneic NK cells. J. Immunol. 2004, 172, 644–650.
[77]
Hsu, K.C.; Keever-Taylor, C.A.; Wilton, A.; Pinto, C.; Heller, G.; Arkun, K.; O'Reilly, R.J.; Horowitz, M.M.; Dupont, B. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood 2005, 105, 4878–4884.
[78]
Leung, W.; Handgretinger, R.; Iyengar, R.; Turner, V.; Holladay, M.S.; Hale, G.A. Inhibitory KIR-HLA receptor-ligand mismatch in autologous haematopoietic stem cell transplantation for solid tumour and lymphoma. Br. J.Cancer 2007, 97, 539–542, doi:10.1038/sj.bjc.6603913.
[79]
Venstrom, J.M.; Zheng, J.; Noor, N.; Danis, K.E.; Yeh, A.W.; Cheung, I.Y.; Dupont, B.; O'Reilly, R.J.; Cheung, N.K.; Hsu, K.C. KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. Clin. Cancer Res. 2009, 15, 7330–7334.
[80]
Miller, J.S.; Soignier, Y.; Panoskaltsis-Mortari, A.; McNearney, S.A.; Yun, G.H.; Fautsch, S.K.; McKenna, D.; Le, C.; Defor, T.E.; Burns, L.J.; et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005, 105, 3051–3057.
Geller, M.A.; Cooley, S.; Judson, P.L.; Ghebre, R.; Carson, L.F.; Argenta, P.A.; Jonson, A.L.; Panoskaltsis-Mortari, A.; Curtsinger, J.; McKenna, D.; et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 2011, 13, 98–107.
[83]
Olson, J.A.; Leveson-Gower, D.B.; Gill, S.; Baker, J.; Beilhack, A.; Negrin, R.S. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 2010, 115, 4293–4301.
[84]
Delgado, D.C.; Hank, J.A.; Kolesar, J.; Lorentzen, D.; Gan, J.; Seo, S.; Kim, K.M.; Shusterman, S.; Gillies, S.D.; Reisfeld, R.A.; 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. 2010, 70, 9554–9661.
[85]
Gillies, S.D.; Lan, Y.; Williams, S.; Carr, F.; Forman, S.; Raubitschek, A.; Lo, K.M. An anti-CD20-IL-2 immunocytokine is highly efficacious in a SCID mouse model of established human B lymphoma. Blood 2005, 105, 3972–3978, doi:10.1182/blood-2004-09-3533.
[86]
Gubbels, J.A.; Gadbaw, B.; Buhtoiarov, I.N.; Horibata, S.; Kapur, A.K.; Patel, D.; Hank, J.A.; Gillies, S.D.; Sondel, P.M.; Patankar, M.S.; et al. Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface. Cancer Immunol. Immun. 2011, 60, 1789–1800.
[87]
Buhtoiarov, I.N.; Neal, Z.C.; Gan, J.; Buhtoiarova, T.N.; Patankar, M.S.; Gubbels, J.A.A.; Hank, J.A.; Yamane, B.; Rakhmilevich, A.L.; Reisfeld, R.A.; et al. Differential internalization of hu14.18-IL2 immunocytokine by NK and tumor cells: Impact on conjugation, cytotoxicity and targeting. J. Leuk. Biol. 2011, 89, 625–638.
[88]
Albertini, M.R.; Hank, J.A.; Gadbaw, B.; Kostlevy, J.; Haldeman, J.; Schalch, H.; Kim, K.M.; Eickhoff, J.; Gillies, S.D.; Sondel, P.M. Phase II Trial of Hu14.18-IL2 for Patients with Metastatic Melanoma. Cancer Immunol. Immun. 2012. in press.
[89]
Gillies, S.D.; Young, D.; Lo, K.-M.; Roberts, S. Biological activity and in vivo clearance of antitumor antibody/cytokine fusion proteins. Bioconjug. Chem. 1993, 4, 230–235, doi:10.1021/bc00021a008.
Johnson, E.E.; Lum, H.D.; Rakhmilevich, A.L.; Schmidt, B.E.; Furlong, M.; Buhtoiarov, I.N.; Hank, J.A.; Raubitschek, A.; Colcher, D.; Reisfeld, R.A.; et al. Intratumoral Immunocytokine Treatment Results in Enhanced Antitumor Activity. Cancer Immunol. Immun. 2008, 57, 1891–1902.
[92]
Weide, B.; Derhovanessian, E.; Pflugfelder, A.; Eigentler, T.K.; Radny, P.; Zelba, H.; Pf？hler, C.; Pawelec, G.; Garbe, C. High response rate after intratumoral treatment with interleukin-2: Results from a phase 2 study in 51 patients with metastasized melanoma. Cancer 2010, 116, 4139–4146.
[93]
Weide, B.; Eigentler, T.K.; Pflugfelder, A.; Leiter, U.; Meier, F.; Bauer, J.; Schmidt, D.; Radny, P.; Pf？hler, C.; Garbe, C. Survival after intratumoral interleukin-2 treatment of 72 melanoma patients and response upon the first chemotherapy during follow-up. Cancer Immunol. Immun. 2011, 60, 487–493.
[94]
Johnson, E.E.; Yamane, B.H.; Lum, H.D.; Buhtoiarov, I.N.; Rakhmilevich, A.L.; Mahvi, D.M.; Gillies, S.D.; Sondel, P.M. Radiofrequency Ablation Combined with KS-IL2 Immunocytokine (EMD 273066) Results in an Enhanced Anti-tumor Effect Against Murine Colon Adenocarcinoma. Clin. Cancer Res. 2009, 15, 4875–4884.
Gillies, S.D.; Lan, Y.; Lo, K.M.; Super, M.; Wesolowski, J. Improving the efficacy of antibody-interleukin 2 fusion proteins by reducing their interaction with Fc receptors. Cancer Res. 1999, 59, 2159–2166.
[97]
Gillies, S.D.; Lo, K.M.; Burger, C.; Lan, Y.; Dahl, T.; Wong, W.K. Improved circulating half-life and efficacy of an antibody-interleukin 2 immunocytokine based on reduced intracellular proteolysis. Clin. Cancer Res. 2002, 8, 210–216.
[98]
Wahlin, B.E.; Aggarwal, M.; Montes-Moreno, S.; Gonzalez, L.F.; Roncador, G.; Sanchez-Verde, L.; Christensson, B.; Sander, B.; Kimby, E. A unifying microenvironment model in follicular lymphoma: outcome is predicted by programmed death-1—Positive, regulatory, cytotoxic, and helper T cells and macrophages. Clin. Cancer Res. 2010, 16, 637–650.
[99]
Shanafelt, A.B.; Lin, Y.; Shanafelt, M.C.; Forte, C.P.; Dubois-Stringfellow, N.; Carter, C.; Gibbons, J.A.; Cheng, S.L.; Delaria, K.A.; Fleischer, R.A. T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nat. Biotechnol. 2000, 18, 1197–1202.
[100]
Gillies, S.D.; Lan, Y.; Hettmann, T.; Brunkhorst, B.; Sun, Y.; Mueller, S.O.; Lo, K.M. A low-toxicity IL-2-based immunocytokine retains antitumor activity despite its high degree of IL-2 receptor selectivity. Clin. Cancer Res. 2011, 17, 3673–3685.
