title: Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine.
abstract: Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8(+) T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8(+) T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8(+) T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8(+) T cells, which led to higher ratios of CD8(+)/Treg and CD8(+)/CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8(+) T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.forename: Sofia
authors.initials: S
authors.lastname: Lyford-Pike
authors.forename: Belinda
authors.initials: B
authors.lastname: Akpeng
authors.forename: Annie
authors.initials: A
authors.lastname: Wu
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: Drew
authors.initials: D
authors.lastname: Hannaman
authors.forename: John R
authors.initials: JR
authors.lastname: Saunders
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.forename: Sara I
authors.initials: SI
authors.lastname: Pai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D053918:Papillomavirus Vaccines; D019444:Vaccines, DNA; D003520:Cyclophosphamide