Harnessing the potential of IL-12 for targeted immunotherapy

GEN-1, an IL-12 DNA plasmid vector formed into nanoparticles with a lipopolymeric delivery system, is the first product designed via the TheraPlas platform technology. TheraPlas has proven to be an effective immunotherapy for treating various types of tumors when utilized in combination with an interleukin-12 (IL-12) plasmid. IL-12 is one of the most active cytokines for stimulating an immune response against cancer. However, when administered as a recombinant protein, the pharmacokinetics of IL-12 requires that it be administered by frequent, large bolus injections, resulting in serious toxicities that limit its use.

See GEN‐1 in action

GEN-1 circumvents toxicity issues typically associated with IL-12

GEN-1 addresses the toxicity issues associated with IL-12. Its nanoparticle profile enables cell transfection followed by persistent, local secretion of IL-12 at therapeutic levels, while avoiding the toxicities associated with recombinant IL-12. Targeted administration directly to the tumor location also helps reduce toxicities.

✓   Local administration to improve targeting
✓   Stimulates the body’s immune system to attack cancer
✓   Plasmid vehicle avoids pitfalls of viral vector
✓   Provides persistent increases in IL-12 levels in tumor microenvironment

Positive clinical results in ovarian, colorectal, and brain cancer

Biological activity, safety and clinical benefits have been demonstrated in platinum-resistant ovarian cancer in multiple clinical studies where GEN-1 was administered as a single agent or as a combination agent with chemotherapy. The highest safe dose from monotherapy and combination therapy studies examined to date has been 80 mg/m2. Preclinical and clinical studies suggest that GEN-1 can be safely and repeatedly administered for the treatment of a variety of tumor types including ovarian, colorectal, and brain cancers.

Evidence of biological activity

IFN-g = interferon gamma; TNF-a = tumor necrosis factor alpha.

Survival rates by dose

Clinical studies using GEN-1

OVATION 2 Study This phase I/II randomized, open label trial is currently underway in newly diagnosed patients. The primary objective of the study is to evaluate safety and compare progression free survival between neoadjuvant chemotherapy (NACT) plus GEN-1 versus standard NACT. This is a randomized, open label, multicenter trial in which eligible subjects will be assigned 1:1 to the treatment and control arms. The phase I portion of the study will determine the dosing for the phase II portion, which will also evaluate safety, efficacy, and biological activity.

OVATION Study This phase I trial in newly diagnosed patients was conducted to determine the maximum tolerated dose (MTD) of GEN-1 as a neoadjuvant therapy to first-line standard of care, followed by surgery. The study also evaluated dose-related biological response to IL-12.

Glioblastoma multiforme (GBM) Preclinical studies have demonstrated that administration of GEN-1 in the brain can lead to an IL-12 expression that lasts for at least 1 month, producing encouraging survival benefits.

Disease applications for GEN-1

Ovarian cancer is the most lethal of gynecological malignancies among women, with an overall 5-year survival rate of 45%. There were approximately 22,000 new cases of ovarian cancer in the United States in 2014 with an estimated 14,000 deaths. Mortality rates for ovarian cancer declined very little in the last 40 years, due to lack of early detection tests and little improvement in treatments.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor. These tumors are often aggressive and infiltrate surrounding brain tissue. GBM has an incidence of 2-3 per 100,000 adults per year and accounts for 52% of all primary brain tumors.