Immunotherapeutic Synergy Between Anti-CD137 mAb and Intratumoral Administration of a Cytopathic Semliki Forest Virus Encoding IL-12

• Published in: Molecular therapy 2012-09, Vol.20 (9), p.1664-1675
• Main Authors: Quetglas, José I, Dubrot, Juan, Bezunartea, Jaione, Sanmamed, Miguel F, Hervas-Stubbs, Sandra, Smerdou, Cristian, Melero, Ignacio
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Antigens; Apoptosis; Apoptosis - drug effects; Cancer therapies; Carcinoma - immunology; Carcinoma - mortality; Carcinoma - therapy; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Clinical trials; Cricetinae; Cytokines; Cytotoxicity; Dendritic cells; Gene Expression - drug effects; Gene therapy; Hepatology; Human papillomavirus; Immunity, Cellular - drug effects; Immunologic Memory - drug effects; Immunotherapy - methods; Injections, Intralesional; Injections, Intravenous; Interleukin-12 - administration & dosage; Interleukin-12 - genetics; Interleukin-12 - immunology; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - immunology; Lung Neoplasms - immunology; Lung Neoplasms - mortality; Lung Neoplasms - therapy; Lymphocytes; Medical research; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - mortality; Melanoma, Experimental - therapy; Mice; Monoclonal antibodies; Original; Semliki Forest virus; Semliki forest virus - genetics; Semliki forest virus - immunology; Skin Neoplasms - immunology; Skin Neoplasms - mortality; Skin Neoplasms - therapy; Survival Rate; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - agonists; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumors; Vectors (Biology)
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2012.56

Intratumoral injection of Semliki Forest virus encoding interleukin-12 (SFV-IL-12) combines acute expression of IL-12 and stressful apoptosis of infected malignant cells. Agonist antibodies directed to costimulatory receptor CD137 (4-1BB) strongly amplify pre-existing cellular immune responses toward weak tumor antigens. In this study, we provide evidence for powerful synergistic effects of a combined strategy consisting of intratumoral injection of SFV-IL-12 and systemic delivery of agonist anti-CD137 monoclonal antibodies (mAbs), which was substantiated against poorly immunogenic B16 melanomas (B16-OVA and B16.F10) and TC-1 lung carcinomas. Effector CD8β+ T cells were sufficient to mediate complete tumor eradications. Accordingly, there was an intensely synergistic in vivo enhancement of cytotoxic T lymphocytes (CTL)-mediated immunity against the tumor antigens OVA and tyrosine-related protein-2 (TRP-2). This train of phenomena led to long-lasting tumor-specific immunity against rechallenge, attained transient control of the progression of concomitant tumor lesions that were not directly treated with SFV-IL-12 and caused autoimmune vitiligo. Importantly, we found that SFV-IL-12 intratumoral injection induces bright expression of CD137 on most tumor-infiltrating CD8+ T lymphocytes, thereby providing more abundant targets for the action of the agonist antibody. This efficacious combinatorial immunotherapy strategy offers feasibility for clinical translation since anti-CD137 mAbs are already undergoing clinical trials and development of clinical-grade SFV-IL-12 vectors is in progress.