title: Therapeutic HPV Cancer Vaccine Targeted to CD40 Elicits Effective CD8+ T-cell Immunity.
abstract: Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (αCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8+and CD4+T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40Tg) mice in vivo The combination of αCD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T cells, particularly CD8+T cells, in hCD40Tg mice. Inclusion of montanide enhanced HPV16.E6/7-specific CD4+, but not CD8+, T-cell responses. Poly(I:C) plus αCD40-HPV16.E6/7 was sufficient to mount both preventative and therapeutic immunity against TC-1 tumors in hCD40Tg mice, significantly increasing the frequency of HPV16-specific CD8+CTLs in the tumors, but not in peripheral blood. In line with this, tumor volume inversely correlated with the frequency of HPV16.E6/7-specific CD8+T cells in tumors, but not in blood. These data suggest that CD40-targeting vaccines for HPV-associated malignancies can provide a highly immunogenic platform with a strong likelihood of clinical benefit. Data from this study offer strong support for the development of CD40-targeting vaccines for other cancers in the future. Cancer Immunol Res; 4(10); 823-34. ©2016 AACR.
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas. Institute of Biomedical Studies, Baylor University, Waco, Texas.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Yin
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Duluc
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas. Institute of Biomedical Studies, Baylor University, Waco, Texas.
authors.forename: HyeMee
authors.initials: H
authors.lastname: Joo
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas. Institute of Biomedical Studies, Baylor University, Waco, Texas.
authors.forename: Chao
authors.initials: C
authors.lastname: Gu
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas.
authors.forename: Richard
authors.initials: R
authors.lastname: Ouedraogo
authors.affiliation: Division of Head and Neck Surgery, Texas Oncology, Baylor University Medical Center, Dallas, Texas.
authors.forename: Lance
authors.initials: L
authors.lastname: Oxford
authors.affiliation: Department of Otolaryngology, Stanford School of Medicine, Palo Alto, California.
authors.forename: Amelia
authors.initials: A
authors.lastname: Clark
authors.affiliation: Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Falguni
authors.initials: F
authors.lastname: Parikh
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Kim-Schulze
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas. Institute of Biomedical Studies, Baylor University, Waco, Texas.
authors.forename: LuAnn
authors.initials: L
authors.lastname: Thompson-Snipes
authors.affiliation: Department of Pathology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea.
authors.forename: Sang-Yull
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas.
authors.forename: Clay
authors.initials: C
authors.lastname: Beauregard
authors.affiliation: Cancer Research Institute, Baylor Scott and White Health, Temple, Texas.
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Woo
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zurawski
authors.affiliation: Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas. Institute of Biomedical Studies, Baylor University, Waco, Texas.
authors.forename: Gerard
authors.initials: G
authors.lastname: Zurawski
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas. Institute of Biomedical Studies, Baylor University, Waco, Texas. sangkono@baylorhealth.edu.
authors.forename: SangKon
authors.initials: S
authors.lastname: Oh
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology*; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053918:Papillomavirus Vaccines / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000998:Antiviral Agents; D019013:CD40 Antigens; D019496:Cancer Vaccines; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; D011070:Poly I-C