Clinical and Immunologic Biomarkers for Histologic Regression of High-Grade Cervical Dysplasia and Clearance of HPV16 and HPV18 after Immunotherapy

Abstract

As previously reported, treatment of high-grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared with only 14.3% in placebo recipients in a randomized phase IIb study. Here, we identify clinical and immunologic characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decision-making for this disease. We analyzed samples taken from cervical swabs, whole blood, and tissue biopsies/resections to determine correlates and predictors of treatment success. At study entry, the presence of preexisting immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment 22 weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137perforinCD8 T cells specific for the HPV genotype causing disease. Increases in cervical mucosal CD137 and CD103 infiltrates were observed only in treated patients. Perforin cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR. Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced premalignancy, with particular emphasis on the upregulation of perforin in the immunotherapy-induced immune response. .

Immune Therapy Targeting E6/E7 Oncogenes of Human Papillomavirus Type 6 (HPV-6) Reduces or Eliminates the Need for Surgical Intervention in the Treatment of HPV-6 Associated Recurrent Respiratory Papillomatosis

“…The necessity for a T cell response of this nature in combating HPV-driven disease has been exemplified in two of our previous clinical trials for DNA-based immunotherapy, both of which were delivered using the CELLECTRA ® device. In the context of HPV-associated cervical dysplasia in a large, double-blind, placebo-controlled Phase 2b trial, clinical response to treatment with VGX-3100 (DNA immunotherapy for targeting E6/E7 of HPV16/18) in the form of regression of lesions concomitant with elimination of HPV infection was statistically associated with the presence of a robust cellular response that included IFN-γ and CD8+ T cells exhibiting phenotypic markers of cytoxicity [25]. Additionally, in another trial investigating treatment of HPV-associated squamous cell cancer of the oropharynx, a patient with metastatic cancer who achieved a complete response to treatment with nivolumab after treatment with MEDI0457 (VGX-3100 + INO-9012) was noted as having a therapy-driven robust expansion of PD1 + cytotoxic T cells [27].…”

“…Importantly, an engineered plasmid IL-12 genetic adjuvant has been shown to enhance immunogenicity in humans when delivered using the CELLECTRA ® device [20,21]. We have established in multiple clinical studies targeting both skin delivery as well as local muscle that delivery of optimized DNA via the CELLECTRA ® device is a highly reproducible method of generating immunity in human beings in a rapid fashion for various purposes ranging from induction prophylactic settings as well as therapeutic approaches [20][21][22][23][24][25][26][27][28].…”

Active Immunoprophylaxis and Vaccine Augmentations Mediated by a Novel Plasmid DNA Formulation

“…**p = 0.0043; *p = 0.0411. mixed 1 min before injection; 0 h). In vivo delivery of the pDNA/Cho ABC co-formulation stored for 24 h at 6°C to the TA muscle in Balb/c mice was associated with a 9.56-fold increase in gene expression (7,223.05 ng/mL) in comparison to the pDNA/ PBS formulation group (755.16 ng/mL; Fig. 4b).…”

“…PLASMID DNA (pDNA)-based gene transfer has emerged as an attractive platform to target infectious disease, 1-6 cancer, [7][8][9][10][11][12][13][14] tissue repair, and regeneration. 15,16 Advances in this technology, specifically in the intramuscular delivery of pDNA by in vivo electroporation (EP), have permitted robust expression of transgenes, offering a viable alternative platform to the use of viral vectors.…”

Synthetic DNA Vaccines Adjuvanted with pIL-33 Drive Liver-Localized T Cells and Provide Protection from Plasmodium Challenge in a Mouse Model

“…Consequently, IL-33 was chosen as a molecular adjuvant for this study. Another strength of the DNA vaccine platform is its ability to drive functional, localized cell-mediated immunity (CMI) in the clinic [47,50]. Prior work studying the immunity from a hepatitis B DNA vaccine showed the ability of this platform to drive vaccine-specific CTLs to traffic to the liver, an organ that is known to be tolerogenic and suppress T cell responses [51].…”