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Enhancing antimelanoma immune responses through apoptosis.
|Title||Enhancing antimelanoma immune responses through apoptosis.|
|Publication Type||Journal Article|
|Year of Publication||2003|
|Authors||Bianco SR, Sun J, Fosmire SP, Hance K, Padilla ML, Ritt MG, Getzy DM, Duke RC, Withrow SJ, Lana S, Matthiesen DT, Dow SW, Bellgrau D, Cutter GR, Helfand SC, Modiano JF|
|Journal||Cancer gene therapy|
|Date Published||2003 Sep|
|Keywords||Animals, Apoptosis, Dog Diseases, Dogs, Fas Ligand Protein, Gene Therapy, Immunotherapy, Leukocytes, Mononuclear, Melanoma, Membrane Glycoproteins, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured|
We examined the feasibility of using tumor apoptosis at accessible sites to enhance antimelanoma immune responses in a model of spontaneous canine melanoma. We show that priming peripheral blood mononuclear cells with apoptotic melanoma cells significantly enhanced autologous and allogeneic lymphokine-activated killing of tumor cells. Since various pathways required for intrinsic apoptosis are often inactivated in melanoma, we used Fas ligand (FasL) overexpression to promote extrinsic apoptosis. FasL induced apoptosis in five of six cell lines. Each of the susceptible lines, but not the resistant one, expressed Fas mRNA. In addition, direct intratumoral administration of FasL DNA to tumor-bearing dogs was safe, with no adverse events reported over 7 days of observation. A reduction of tumor burden was seen in three of five dogs treated. The reduction of tumor volume was correlated with Fas expression by the tumors, although one dog with a Fas-negative tumor survived for 82 weeks after treatment. Our data show that overexpression of FasL is suitable to promote apoptosis of Fas(+) melanomas, and support the notion that priming immune responder cells with apoptotic tumor cells may enhance antitumor responses. The results also suggest that intratumoral administration of FasL offers a safe route for therapeutic gene delivery.
|Alternate Journal||Cancer Gene Ther.|