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Objectives Assessment of the safety and efficacy and immunogenicity of VGX-3100 in women with biopsy-proven CIN2/3 with concurrent HPV16 and/or HPV18 infection. Methods The randomized, placebo-controlled, double-blind study, which was stratified by age and severity of CIN, evaluated cervical tissue changes after three 6 mg intramuscular doses of VGX-3100 followed by electroporation with Inovio’s CELLECTRA2000 device at weeks 0, 4, and 12. Results Among 167 vaccinated women, the study met its primary efficacy endpoint; the percentage of patients who had regression of CIN2/3 to CIN1 or no disease at 6 months post third dose was significantly higher in the VGX-3100 group compared to placebo (p=0.034). In addition, the trial demonstrated the ability of VGX-3100 to clear HPV infection concurrent with regression of CIN2/3 (p=0.003). Post-hoc immune analysis also revealed significantly elevated immune responses in treated patients who had CIN2/3 regression concurrent with HPV clearance when compared to those who did not. This included the presence of CD8+ T cells in the blood exhibiting CD137 expression concurrent with perforin (p=0.032) as well as perforin in addition to granzyme A (p=0.036) as well as an influx of CD8+ T cells into cervical tissue (p=0.008). Conclusion The successful phase 2b results represent a significant milestone in the development of active immunotherapies to treat HPV-related dysplasia and cancer. The data generated from the trial reveal statistically significant correlations between antigen specific T cell activity and clinical benefits afforded by VGX-3100. Thus VGX-3100 has the potential to provide an important alternative or adjunct to surgery in treating CIN 2/3 based on HPV specific T cell activity.

Here we report the results of a Phase II study assessing the safety and efficacy of VGX-3100 in 167 women with biopsy-proven CIN 2/3 with concurrent HPV16/18 infection. The randomized, placebo-controlled, double-blind study evaluated cervical tissue changes after three 6 mg intramuscular doses of VGX-3100 followed by electroporation (EP) with Inovio’s CELLECTRA®2000 device at weeks 0, 4, and 12. Cervical tissue was examined before treatment and 9 months later. The study met its primary efficacy endpoint; the percentage of patients who had regression of CIN 2/3 to CIN 1 or no disease at 6 months post third dose was significantly higher in the VGX-3100 group compared to the placebo group (p=0.017). In addition, the trial demonstrated the ability of VGX-3100 clear HPV infection concurrent with regression of CIN lesions. The study also explored humoral and cellular immune responses to VGX-3100 in blood samples taken periodically during the trial. ELISA as well as IFN-g ELISpot results revealed significantly higher responses in the VGX-3100 treated group than in the placebo group, suggesting that VGX-3100 was able to robustly engage the patients’ immune system. Altogether, the successful phase 2 results represent a significant milestone in the development of active immunotherapies not only to robustly engage the immune system but also to treat cancer and infectious diseases and have the potential to provide physicians an important alternative to surgery to treat CIN 2/3 disease.

In the thymus, Notch signaling is known to be essential for T-lymphopoiesis, with the Notch ligand Delta like 4 (Dll4) being uniquely involved in this process. However, using stromal cell cultures, either Dll4 or Dll1 has been shown to support T-lymphopoiesis. To address which Dll is more effective at inducing hematopoietic progenitor cells to give rise to T-lineage cells in vitro, we generated OP9 cells expressing a series of incrementally discrete and equivalent levels of Dll1 or Dll4. In keeping with previous findings, OP9 cells expressing high levels of either Dll1 or Dll4 gave rise to T-lineage cells with similar efficacy, and prevented the differentiation of B- and myeloid-lineage cells. However, at limiting levels of Dll expression, Dll4 maintained its ability to inhibit B-lineage choice and induce T-lineage commitment and differentiation at lower levels of expression than Dll1. This manifest property of Dll4 is evident despite its lower levels of steady-state surface expression than Dll1 on OP9 cells. The heightened effectiveness of Dll4 over Dll1 also corresponded to the induction of expression of Notch target genes, and inhibition of B- and myeloid-specific transcription factors. Furthermore, OP9 cells expressing levels of Dll4 equivalent to those present in thymic epithelial cells gave rise to T-lineage cells, as expected, but were also permissive for the differentiation of myeloid cells, while still inhibiting the generation of B-lineage cells.