Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients

Abstract

Here, we demonstrate that electroporation-enhanced immunization with a rationally designed HPV DNA vaccine (GX-188E), preferentially targeting HPV antigens to dendritic cells, elicits a significant E6/E7-specific IFN-γ-producing T-cell response in all nine cervical intraepithelial neoplasia 3 (CIN3) patients. Importantly, eight out of nine patients exhibit an enhanced polyfunctional HPV-specific CD8 T-cell response as shown by an increase in cytolytic activity, proliferative capacity and secretion of effector molecules. Notably, seven out of nine patients display complete regression of their lesions and viral clearance within 36 weeks of follow up. GX-188E administration does not elicit serious vaccine-associated adverse events at all administered doses. These findings indicate that the magnitude of systemic polyfunctional CD8 T-cell response is the main contributing factor for histological, cytological and virological responses, providing valuable insights into the design of therapeutic vaccines for effectively treating persistent infections and cancers in humans.

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

“…Felber, unpublished observations) responses, which efficiently disseminate to mucosal tissues (39,54). In addition, the recent demonstration of therapeutic efficacy of a human papilloma virus vaccine delivered by DNA or electroporation in a Phase IIB randomized study in humans (55)(56)(57) demonstrates the efficacy of a pDNA platform in inducing mucosal T cell responses in humans. This offers the possibility of using a pDNA vaccination targeting the CE in a therapeutic setting against HIV infection, because this vaccine regimen induces potent cytotoxic T cell responses targeting the presumed weakness of the virus.…”

Celecoxib promotes degranulation of CD8+ T cells in HPV-induced lesions of K14-HPV16 transgenic mice

“…In fact, infiltration by these cells in HPV-associated lesions has already been shown to lead to regression [8,30]. CTL infiltration drives the response induced by an experimental therapeutic vaccine in patients with cervical intraepithelial lesions [14] and correlates with a better prognosis in patients with HPV-positive head and neck cancer [15][16][17].…”

“…The results presented herein suggest that celecoxib induces augmented CTL degranulation in HPV-induced lesions, possibly contributing to prevent malignant progression in this animal model. Enhancing CD8 + T cell activation seems a promising therapeutic strategy considering the role played by CTL in the regression of HPV-associated cervical lesions [8], in HPV-positive head and neck cancer [15][16][17] and the response to vaccines [14], and COX-2 inhibitors may prove useful for this purpose.…”

“…FAS-FASL or TRAIL) or following interferon-γ-dependent mechanisms [11][12][13]. In particular, CTL are critical to control cervical lesions and were recently demonstrated to drive the immune response in patients following the administration of an experimental therapeutic vaccine [14].…”

Immunotherapy against cancer-related viruses

“…In general, HPV vaccines are safe and effective as prophylaxis against infection [114][115], but have no activity against established disease since they lack specificity for E6/E7, the only viral proteins expressed in HPV-associated tumors. Therapeutic vaccines are currently under investigation [116].…”