Local IL-4 delivery enhances immune reactivity to murine tumors: gene therapy in combination with IL-2.
Tumor cells transduced with the IL-4 gene demonstrate reduction of growth associated with macrophage and eosinophilic infiltrates, generation of cytotoxic T-cells, and protective immunity. Using murine IL-4 retroviral vectors, murine fibroblasts and tumors that produce from 50 to 5000 U of IL-4/10(6) cells per 24 hours as determined by ELISA and bioassay were successfully transduced. In blinded studies using C57BL/6 and BALB/c mice, we have shown that tumor growth can be inhibited (mean delay of 10 days compared with controls; P < .05) and in some cases, completely suppressed by the coinjection of viable tumor with IL-4-producing fibroblasts (tumor free > 100 days; P < .001). Animals that are able to reject an initial tumor inoculate can also completely reject subsequent parental tumor challenge of 10(5) cells (P < .001) while challenge of 10(6) parental tumor cells results in a significant delay of tumor induction (P < .05). In addition, immunization with IL-4 transduced fibroblasts and irradiated tumor cells resulted in complete suppression of parental tumor challenge in animals that received the high-dose IL-4 delivery. Finally coadministration of systemic IL-2 led to enhancement of IL-4 gene therapy resulting in a 20-day delay of preestablished tumor growth compared with controls (P < .05).
Pippin
B A
BA
Department of Surgery, University of Pittsburgh Medical Center, Pennsylvania, USA.
Rosenstein
M
M
Jacob
W F
WF
Chiang
Y
Y
Lotze
M T
MT
D000818:Animals; D002478:Cells, Cultured / Q000637:transplantation; D003131:Combined Modality Therapy; D005347:Fibroblasts / Q000528:radiation effects / Q000637:transplantation*; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006084:Graft Rejection; D007114:Immunization; D007155:Immunologic Factors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000637:transplantation
D007155:Immunologic Factors; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4