title: SA-4-1BBL as the immunomodulatory component of a HPV-16 E7 protein based vaccine shows robust therapeutic efficacy in a mouse cervical cancer model.
abstract: Cervical cancer is the leading cause of cancer-related deaths among women worldwide. Current prophylactic vaccines based on HPV (Human papillomavirus) late gene protein L1 are ineffective in therapeutic settings. Therefore, there is an acute need for the development of therapeutic vaccines for HPV associated cancers. The HPV E7 oncoprotein is expressed in cervical cancer and has been associated with the cellular transformation and maintenance of the transformed phenotype. As such, E7 protein represents an ideal target for the development of therapeutic subunit vaccines against cervical cancer. However, the low antigenicity of this protein may require potent adjuvants for therapeutic efficacy. We recently generated a novel chimeric form of the 4-1BBL costimulatory molecule engineered with core streptavidin (SA-4-1BBL) and demonstrated its safe and pleiotropic effects on various cells of the immune system. We herein tested the utility of SA-4-1BBL as the immunomodulatory component of HPV-16 E7 recombinant protein based therapeutic vaccine in the E7 expressing TC-1 tumor as a model of cervical cancer in mice. A single subcutaneous vaccination was effective in eradicating established tumors in approximately 70% of mice. The therapeutic efficacy of the vaccine was associated with robust primary and memory CD4(+) and CD8(+) T cell responses, Th1 cytokine response, infiltration of CD4(+) and CD8(+) T cells into the tumor, and enhanced NK cell killing. Importantly, NK cells played an important role in vaccine mediated therapy since their physical depletion compromised vaccine efficacy. Collectively, these data demonstrate the utility of SA-4-1BBL as a new class of multifunctional immunomodulator for the development of therapeutic vaccines against cancer and chronic infections.
authors.affiliation: Institute for Cellular Therapeutics, Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Sharma
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: MacLeod
authors.forename: Rich-Henry
authors.initials: RH
authors.lastname: Schabowsky
authors.forename: Shravan
authors.initials: S
authors.lastname: Madireddi
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D003001:Cloning, Molecular; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D050725:Papillomavirus E7 Proteins / Q000276:immunology*; D030361:Papillomavirus Infections / Q000276:immunology / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000276:immunology*; D019809:Streptavidin / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control* / Q000821:virology; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D019496:Cancer Vaccines; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D022223:Vaccines, Subunit; C059731:oncogene protein E7, Human papillomavirus type 16; D019809:Streptavidin