Human papillomavirus (HPV) has been implicated in the pathogenesis of 15% to 23% of head and neck... more Human papillomavirus (HPV) has been implicated in the pathogenesis of 15% to 23% of head and neck squamous cell carcinomas as well as most oropharyngeal carcinomas. The viral oncoproteins E6 and E7 are expressed in HPV-positive tumor cells and therefore provide ideal targets for tumor immunotherapy. Because of its unique ability to induce a cellular immune response, the intracellular bacteria Listeria monocytogenes has been studied as a potential HPV-positive tumor vaccine. To present a new recombinant strain of L monocytogenes that is effective in treating HPV-positive tumors in a murine model. A new recombinant L monocytogenes vaccine, Lm-ActA-E7, was designed by transforming an attenuated Listeria strain with an E7 expression cassette. The cassette consists of the HPV-16 E7 sequence fused to the Listeria protein ActA. The resultant strain of bacteria secretes E7 antigen as a fusion protein with ActA. Tumors were established in C57BL/6 mice with a syngeneic HPV-positive cell line prior to treatment with vaccine. The Lm-ActA-E7 vaccine was administered intraperitoneally to the mice 5 days after tumors were established. A booster dose was administered 7 days after the first dose. Tumor progression was measured in 2 dimensions periodically after the vaccination. In C57BL/6 mice, the administration of Lm-ActA-E7 caused the complete regression of HPV-positive tumors in 6 of 8 mice tested. A cytotoxic T-lymphocyte assay revealed that administration of the vaccine caused the generation of cytotoxic T cells specific for E7. Our results demonstrate the ability of a new Listeria-based vaccine to generate a specific antitumor T-cell response and cause the regression of HPV-positive tumors in a murine model.
To test whether an E7 peptide/CpG vaccine is effective in preventing and treating human papilloma... more To test whether an E7 peptide/CpG vaccine is effective in preventing and treating human papillomavirus-positive tumors in a murine model. First, an E7 peptide/CpG vaccine was administered systemically on days -14 and -7, and tumor cells were injected subcutaneously on day 0. Second, tumor cells were injected on day 0, and vaccine was administered on days 7, 14, and 21. Tumor size was measured 3 times per week. A tetramer assay was used to assess the presence of activated, E7-specific lymphocytes in spleen and tumor cells harvested from mice treated with a similar vaccination regimen. In the prophylactic study, 75% of mice injected with E7 peptide/CpG resisted tumor formation. In the therapeutic setting, tumors initially regressed and experienced delayed progression when compared with controls. Survival rates improved in E7/CpG-vaccinated mice. Tetramer analysis detected increased numbers of activated, E7-specific lymphocytes in the spleens and tumors of animals treated with the experimental vaccine when compared with controls. The use of CpG motifs as an adjunct to peptide-based immunotherapy has potential impact on the treatment of human papillomavirus-associated cancers.
Human papillomavirus (HPV) has been implicated in the pathogenesis of 15% to 23% of head and neck... more Human papillomavirus (HPV) has been implicated in the pathogenesis of 15% to 23% of head and neck squamous cell carcinomas as well as most oropharyngeal carcinomas. The viral oncoproteins E6 and E7 are expressed in HPV-positive tumor cells and therefore provide ideal targets for tumor immunotherapy. Because of its unique ability to induce a cellular immune response, the intracellular bacteria Listeria monocytogenes has been studied as a potential HPV-positive tumor vaccine. To present a new recombinant strain of L monocytogenes that is effective in treating HPV-positive tumors in a murine model. A new recombinant L monocytogenes vaccine, Lm-ActA-E7, was designed by transforming an attenuated Listeria strain with an E7 expression cassette. The cassette consists of the HPV-16 E7 sequence fused to the Listeria protein ActA. The resultant strain of bacteria secretes E7 antigen as a fusion protein with ActA. Tumors were established in C57BL/6 mice with a syngeneic HPV-positive cell line prior to treatment with vaccine. The Lm-ActA-E7 vaccine was administered intraperitoneally to the mice 5 days after tumors were established. A booster dose was administered 7 days after the first dose. Tumor progression was measured in 2 dimensions periodically after the vaccination. In C57BL/6 mice, the administration of Lm-ActA-E7 caused the complete regression of HPV-positive tumors in 6 of 8 mice tested. A cytotoxic T-lymphocyte assay revealed that administration of the vaccine caused the generation of cytotoxic T cells specific for E7. Our results demonstrate the ability of a new Listeria-based vaccine to generate a specific antitumor T-cell response and cause the regression of HPV-positive tumors in a murine model.
To test whether an E7 peptide/CpG vaccine is effective in preventing and treating human papilloma... more To test whether an E7 peptide/CpG vaccine is effective in preventing and treating human papillomavirus-positive tumors in a murine model. First, an E7 peptide/CpG vaccine was administered systemically on days -14 and -7, and tumor cells were injected subcutaneously on day 0. Second, tumor cells were injected on day 0, and vaccine was administered on days 7, 14, and 21. Tumor size was measured 3 times per week. A tetramer assay was used to assess the presence of activated, E7-specific lymphocytes in spleen and tumor cells harvested from mice treated with a similar vaccination regimen. In the prophylactic study, 75% of mice injected with E7 peptide/CpG resisted tumor formation. In the therapeutic setting, tumors initially regressed and experienced delayed progression when compared with controls. Survival rates improved in E7/CpG-vaccinated mice. Tetramer analysis detected increased numbers of activated, E7-specific lymphocytes in the spleens and tumors of animals treated with the experimental vaccine when compared with controls. The use of CpG motifs as an adjunct to peptide-based immunotherapy has potential impact on the treatment of human papillomavirus-associated cancers.
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