Results of Celsion’s OVATION 1 Study with GEN-1 in Patients with Advanced Ovarian Cancer Published in the Journal of Clinical Cancer Research
Data show dose-dependent suppression of immune-suppressive agents
GEN-1 stimulates the immune system through the production of CD4 and CD8 cells
Chemotherapy Response Score tripled in the two highest doses of GEN-1 and is double that of chemotherapy alone
GEN-1 is a DNA-based interleukin-12 (IL-12) immunotherapy currently in Phase I/II clinical development for the localized treatment of advanced ovarian cancer (the OVATION 2 Study). GEN-1 is an immunotherapy that produces safe and durable local levels of IL-12, a pluripotent cytokine associated with the stimulation of innate and adaptive immune response against cancer. The GEN-1 nanoparticle comprises a DNA plasmid encoding IL-12 gene and a synthetic polymer facilitating plasmid delivery vector.
The OVATION 1 Study enrolled 18 patients with newly diagnosed stage IIIC and IV epithelial ovarian cancer in a standard 3+3 dose-escalation design testing four GEN-1 doses (36 mg/m2, 47 mg/m2, 61 mg/m2 and 79mg/m2) in combination with NACT (carboplatin-paclitaxel). There were 15 patients evaluable for safety, and 14 underwent interval debulking and were evaluable for Response Evaluation Criteria in Solid Tumors (RECIST).
As previously reported, there were no dose-limiting toxicities. As shown in the chart below, in the two highest doses of GEN-1 the objective response rate was 100% and the R0 resection rate was 88%. Newly published data show the chemotherapy response score (CRS), which is analyzed in this paper for the first time, was 50% in the two highest doses of GEN-1, compared with 28% from a major publication evaluating CRS scoring. The chemotherapy response score is a three-tier standardized scoring system for histological tumor regression into complete/near complete (CRS 3), partial (CRS 2) and no/minimal (CRS 1) response based on omental examination. Like R0 resection rates, CRS 3 response is believed to be a predictor of progression-free survival.
Clinical Responses: Tumor Response, Surgical Outcome, Pathological Response and Chemotherapy Response Score with NAC/GEN-1 escalating doses
|Radiographic Response||Total (n)||Cohort 1
|Objective Response Rate||67||%||100||%|
|R0 Resection Rate||33||%||88||%|
|CRS 3 Rate||17||%||50||%|
Commenting on the abstract,
Translational Responses: IL-12 and IFN-γ Levels, Response to Immune-Suppressive Agents; Ratio of CD8+ cells to Immune Suppressive Agents
Results from translational studies show the following:
- A dose-dependent increase in immunostimulatory cytokines IL-12 and its downstream cytokine IFN-γ in ascitic fluid. The anticancer effects of these cytokines are widely recognized in human malignancies.
- The proportion of myeloid dendritic cells in the peritoneal fluid trended higher (3.1-fold) accompanied by a similar 3.0-fold rise in CD8+ cells.
- GEN-1 appeared to reduce four immunosuppressive signals (Foxp3, IDO1, PD-1 and PD-L1) within the tumor microenvironment, a trend not seen with NAC therapy alone.
- GEN-1 also appeared to stimulate the body’s immune system through the production of CD4 and CD8 cells.
- GEN-1 gene therapy was associated with an apparent increase in the cytotoxic state of T cells within the tumor microenvironment as indicated by the increases in the ratios of CD8+/CD4+ and CD8+/Treg cells. Indeed, higher CD8+/CD4+ T cell and CD8+/Treg ratios are considered prognostic for prolonged survival.
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About Epithelial Ovarian Cancer
Epithelial ovarian cancer (EOC) is the 5th deadliest malignancy among women in
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