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P181 Combination Tumor Antigen–Targeted Immunotherapy in HPV-16–Positive Head and Neck Squamous Cell Carcinoma

P181 Combination Tumor Antigen–Targeted Immunotherapy in HPV-16–Positive Head and Neck Squamous... Objective: To show that E6-induced proteasomal degradation of p53 in human papillomavirus (HPV) 16–positive head and neck squamous cell carcinoma enhances cytotoxic T-lymphocyte recognition and lysis mediated by increased HLA-A2-p53(264-272) complexes. By directly targeting E7 and p53, we can increase efficacy of adjuvant immunotherapy by avoiding viral mutation and the potential loss of a target. Design: Adjuvant treatment was 5% imiquimod cream (Aldara) or aqueous imiquimod, a toll-like receptor 7 agonist and Food and Drug Administration–approved topical immunomodulatory treatment for HPV-associated warts. Initial in vivo work with murine H2-Kb and -Db restricted peptides, p53(158-166) and E7(49-57), respectively, compared subcutaneous delivery with or without subcutaneous aqueous imiquimod. Current in vivo vaccination models use the HLA-A2 restricted peptides E7(11-20) and p53(261-269), the murine homologue of human HLA-A2 restricted p53(264-272). Results: Interferon gamma enzyme-linked immunospot assay showed enhanced antigen-specific recognition and reactivity after vaccinating with both Kb and Db peptides, which improved the effect of imiquimod. The same regimen exhibited improved in vitro recognition and reactivity by splenocytes in mice vaccinated against an HLA-A2–positive HPV-16 E6 and E7–transformed murine carcinoma cell line, TC-1/A2. With the HLA-A2–restricted p53 and E7 peptides, improved tumor protection was observed from groups receiving Aldara with both peptides or p53(261-269) alone. Tumor protection with Aldara and p53(261-269) alone was greater than when vaccinating with both peptides and almost identical to that seen after vaccination with both peptides and Montanide. Conclusions: Our work supports the use of targeting this specific combination of peptides as well as the feasibility and efficacy of using a topical agent that can serve the dual role of vehicle and adjuvant. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Otolaryngology - Head & Neck Surgery American Medical Association

P181 Combination Tumor Antigen–Targeted Immunotherapy in HPV-16–Positive Head and Neck Squamous Cell Carcinoma

P181 Combination Tumor Antigen–Targeted Immunotherapy in HPV-16–Positive Head and Neck Squamous Cell Carcinoma

Abstract

Objective: To show that E6-induced proteasomal degradation of p53 in human papillomavirus (HPV) 16–positive head and neck squamous cell carcinoma enhances cytotoxic T-lymphocyte recognition and lysis mediated by increased HLA-A2-p53(264-272) complexes. By directly targeting E7 and p53, we can increase efficacy of adjuvant immunotherapy by avoiding viral mutation and the potential loss of a target. Design: Adjuvant treatment was 5% imiquimod cream (Aldara) or aqueous imiquimod, a...
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Publisher
American Medical Association
Copyright
Copyright © 2006 American Medical Association. All Rights Reserved.
ISSN
0886-4470
eISSN
1538-361X
DOI
10.1001/archotol.132.8.900-b
Publisher site
See Article on Publisher Site

Abstract

Objective: To show that E6-induced proteasomal degradation of p53 in human papillomavirus (HPV) 16–positive head and neck squamous cell carcinoma enhances cytotoxic T-lymphocyte recognition and lysis mediated by increased HLA-A2-p53(264-272) complexes. By directly targeting E7 and p53, we can increase efficacy of adjuvant immunotherapy by avoiding viral mutation and the potential loss of a target. Design: Adjuvant treatment was 5% imiquimod cream (Aldara) or aqueous imiquimod, a toll-like receptor 7 agonist and Food and Drug Administration–approved topical immunomodulatory treatment for HPV-associated warts. Initial in vivo work with murine H2-Kb and -Db restricted peptides, p53(158-166) and E7(49-57), respectively, compared subcutaneous delivery with or without subcutaneous aqueous imiquimod. Current in vivo vaccination models use the HLA-A2 restricted peptides E7(11-20) and p53(261-269), the murine homologue of human HLA-A2 restricted p53(264-272). Results: Interferon gamma enzyme-linked immunospot assay showed enhanced antigen-specific recognition and reactivity after vaccinating with both Kb and Db peptides, which improved the effect of imiquimod. The same regimen exhibited improved in vitro recognition and reactivity by splenocytes in mice vaccinated against an HLA-A2–positive HPV-16 E6 and E7–transformed murine carcinoma cell line, TC-1/A2. With the HLA-A2–restricted p53 and E7 peptides, improved tumor protection was observed from groups receiving Aldara with both peptides or p53(261-269) alone. Tumor protection with Aldara and p53(261-269) alone was greater than when vaccinating with both peptides and almost identical to that seen after vaccination with both peptides and Montanide. Conclusions: Our work supports the use of targeting this specific combination of peptides as well as the feasibility and efficacy of using a topical agent that can serve the dual role of vehicle and adjuvant.

Journal

Archives of Otolaryngology - Head & Neck SurgeryAmerican Medical Association

Published: Aug 1, 2006

Keywords: immunotherapy,head and neck squamous cell carcinoma,tumor antigens,human papillomavirus 16

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