Immunotherapeutic synergy between anti-CD137 mAb and intratumoral administration of a cytopathic Semliki Forest virus encoding IL-12.
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 CD8(β)(+) 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.
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Navarra, Spain.
José I
JI
Quetglas
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Navarra, Spain.
Juan
J
Dubrot
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Navarra, Spain.
Jaione
J
Bezunartea
Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain.
Miguel F
MF
Sanmamed
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Navarra, Spain.
Sandra
S
Hervas-Stubbs
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Navarra, Spain. Electronic address: csmerdou@unav.es.
Cristian
C
Smerdou
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Navarra, Spain; Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain. Electronic address: imelero@unav.es.
Ignacio
I
Melero
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002277:Carcinoma / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D045744:Cell Line, Tumor; D006224:Cricetinae; D015870:Gene Expression / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D015552:Injections, Intralesional; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D051379:Mice; D012672:Semliki forest virus / Q000235:genetics / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists / Q000276:immunology
D000911:Antibodies, Monoclonal; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D018664:Interleukin-12; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase