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PurposeSystemic 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 designAnalysis 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.ResultsCombined 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.ConclusionsCombination 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.

Type

Journal article

Journal

Clinical cancer research : an official journal of the American Association for Cancer Research

Publication Date

09/2003

Volume

9

Pages

3546 - 3554

Addresses

Centro de Investigación Médica Aplicada (CIMA), Facultad de Medicina, Gene Therapy Unit, Universidad de Navarra, 31008 Pamplona, Spain. imelero@unav.es

Keywords

T-Lymphocytes, CD8-Positive T-Lymphocytes, T-Lymphocytes, Cytotoxic, Cell Line, Tumor, Animals, Mice, Inbred C57BL, Mice, Transgenic, Humans, Mice, Adenoviridae, Peptides, Cell Adhesion Molecules, Antigens, CD, Interleukin-12, Antibodies, Monoclonal, Cross-Linking Reagents, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Cell Separation, Gene Transfer Techniques, Neoplasm Transplantation, Cell Death, Time Factors, Interferon-gamma