IL-12 and IL-27 sequential gene therapy via intramuscular electroporation delivery for eliminating distal aggressive tumors.
Eradication of residual malignancies and metastatic tumors via a systemic approach is the key for successfully treating cancer and increasing cancer patient survival. Systemic administration of IL-12 protein in an acute large dose is effective but toxic. Systemic administration of IL-12 gene by persistently expressing a low level of IL-12 protein may reduce the systemic toxicity but only eradicates IL-12-sensitive tumors. In this study, we discovered that sequential administration of IL-12- and IL-27-encoding DNA, referred to as sequential IL-12-->IL-27 (IL-12 administration followed by IL-27 administration 10 d after) gene therapy, not only eradicated IL-12-sensitive CT26 tumors from 100% of mice but also eradicated the highly malignant 4T1 tumors from 33% of treated mice in multiple independent experiments. This IL-12-->IL-27 sequential gene therapy is not only superior to IL-12-encoding plasmid DNA given a total of two times at a 10-d interval sequential gene therapy for eliminating tumors but also for inducing CTL activity, increasing T cell infiltration into tumors, and yielding a large number of tumor-specific IFN-gamma-positive CD8 T cells. Notably, depletion of either T or NK cells during the IL-27 treatment phase reverses tumor eradication, suggesting an NK cell requirement for this sequential gene therapy-mediated tumor eradication. Both reversal of the administration sequence and coadministration of IL-12 and IL-27 impaired tumor eradication in 4T1 tumor-bearing mice. This IL-12-->IL-27 sequential gene therapy, via sequential administration of IL-12- and IL-27-encoding plasmid DNA into tumor-bearing mice through i.m. electroporation, provides a simple but effective approach for eliminating inaccessible residual tumors.
School of Medicine, Institute of Medical Science, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Shiguo
S
Zhu
Dean Anthony
DA
Lee
Shulin
S
Li
D000818:Animals; D045744:Cell Line, Tumor; D018274:Electroporation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden
C486767:Il27 protein, mouse; D007378:Interleukins; D018664:Interleukin-12; D007371:Interferon-gamma