Interleukin 12 gene therapy of MHC-negative murine melanoma metastases.
Immunological gene therapy of cancer relies heavily on the activation of T cells, but tumors with defects in MHC gene expression are not recognized by MHC-restricted T cells. To investigate the potential of cytokine genes for the therapy of MHC-negative tumors, we transduced B78H1, a class I-negative murine melanoma clone, with a polycistronic vector carrying murine interleukin (IL)-12 genes. The clones studied produced 400-25,000 pg/ml IL-12; their in vitro growth properties were similar to those of parental cells. A complete inhibition of growth was observed in vivo both after s.c. and i.v. administration of all IL-12 clones. IL-12-transduced cells were also used as a therapeutic vaccine in mice bearing micrometastases by nontransduced parental cells. A significant (80-90%) reduction in the number of lung nodules was obtained. Immunohistochemical analysis and studies in immunocompromised hosts showed that T cells and natural killer cells had a significant role in the elimination of IL-12-releasing cells. In situ hybridization with cytokine probes detected a strong increase in the proportion of leukocytes positive for IFN-gamma, tumor necrosis factor alpha, IL-1beta, and IFN-inducible protein 10 at the site of rejection of IL-12-engineered tumor cells. However, it was clear that the loss of in vivo growth was also due to T-cell- and natural killer cell-independent factors, possibly related to the antiangiogenic properties of IL-12. In conclusion, tumor therapy based on IL-12 gene transduction was effective on a MHC-negative metastatic tumor, suggesting a possible application to MHC-defective human neoplasms.
Nanni
P
P
Institute for Cancer Research, University of Bologna, Italy. nanni@cancer.unibo.it
Rossi
I
I
De Giovanni
C
C
Landuzzi
L
L
Nicoletti
G
G
Stoppacciaro
A
A
Parenza
M
M
Colombo
M P
MP
Lollini
P L
PL
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015316:Genetic Therapy; D006183:H-2 Antigens; D016867:Immunocompromised Host; D018664:Interleukin-12 / Q000235:genetics*; D008175:Lung Neoplasms / Q000556:secondary; D008285:Major Histocompatibility Complex; D008297:Male; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic; D014161:Transduction, Genetic
D019496:Cancer Vaccines; D006183:H-2 Antigens; D018664:Interleukin-12