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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Terapia génica y Hepatología > Inmunología terapia génica > DA - CIMA - Terapia génica y Hepatología - Inmunología terapia génica - Artículos de revista >

Anti-ICAM-2 monoclonal antibody synergizes with intratumor gene transfer of interleukin-12 inhibiting activation-induced T-cell death
Authors: Melero, I. (Ignacio)
Gabari, I. (Izaskun)
Tirapu, I. (Íñigo)
Arina, A. (Ainhoa)
Mazzolini, G. (Guillermo)
Baixeras, E. (Elena)
Feijoo, E. (Esperanza)
Alfaro, C. (Carlos)
Qian, C. (Cheng)
Prieto, J. (Jesús)
Keywords: Antibodies, Monoclonal/chemistry
Antigens, CD/chemistry
Antigens, CD/immunology
Cell Adhesion Molecules/chemistry
Cell Adhesion Molecules/immunology
Gene Transfer Techniques
Interleukin-12/metabolism
T-Lymphocytes/cytology
Issue Date: 2003
Publisher: American Association for Cancer Research
Publisher version: http://clincancerres.aacrjournals.org/content/9/10/3546
ISSN: 1557-3265
Citation: Melero I, Gabari I, Tirapu I, Arina A, Mazzolini G, Baixeras E, et al. Anti-ICAM-2 monoclonal antibody synergizes with intratumor gene transfer of interleukin-12 inhibiting activation-induced T-cell death. Clin Cancer Res 2003 Sep 1;9(10 Pt 1):3546-3554.
Abstract
PURPOSE: Systemic treatment with an anti-ICAM-2 monoclonal antibody (mAb; EOL4G8) eradicates certain established mouse tumors through a mechanism dependent on the potentiation of a CTL-mediated response. However, well-established tumors derived from the MC38 colon carcinoma cell line were largely refractory to this treatment as well as to intratumor injection of a recombinant adenovirus encoding interleukin-12 (IL-12; AdCMVIL-12). We sought to design combined therapy strategies with AdCMVIL-12 plus anti-ICAM-2 mAbs and to identify their mechanism of action. EXPERIMENTAL DESIGN: Analysis of antitumor and toxic effects were performed with C57BL/6 mice bearing established MC38 tumors. Anti-ovalbumin T-cell receptor transgenic mice and tumors transfected with this antigen were used for in vitro and in vivo studies on activation-induced cell death (AICD) of CD8(+) T cells. RESULTS: Combined treatment with various systemic doses of EOL4G8 mAb plus intratumor injection of AdCMVIL-12 induced complete regression of MC38 tumors treated 7 days after implantation. Unfortunately, most of such mice succumbed to a systemic inflammatory syndrome that could be prevented if IFN-gamma activity were neutralized once tumors had been rejected. Importantly, dose reduction of EOL4G8 mAb opened a therapeutic window (complete cure of 9 of 18 cases without toxicity). We also show that ICAM-2 ligation by EOL4G8 mAb on activated CTLs prevents AICD, thus extending IFN-gamma production. CONCLUSIONS: Combination of intratumor gene transfer of IL-12and systemic anti-ICAM-2 mAb display synergistic therapeutic and toxic effects. CTL life extension resulting from AICD inhibition by anti-ICAM-2 mAbs is the plausible mechanism of action.
Permanent link: http://hdl.handle.net/10171/21777
Appears in Collections:DA - Medicina - Medicina Interna - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Inmunología terapia génica - Artículos de revista

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