Preclinical Studies of Product Candidates

TheraPlasTM in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and the most aggressive in the central nervous system, with only one-third of patients surviving for 1 year and less than 5% living beyond 5 years. Current therapies, which are directly cytotoxic to tumor cells, may be improved upon by treatments that also target the protumorigenic tumor microenvironment.

Local delivery of interleukin-12 (IL-12) genes by GEN-1, in combination with the standard of care, offers a novel approach to GBM treatment. Local production of IL-12 by GEN-1 is anticipated to modify the tumor microenvironment through activation of tumor-killing lymphocytes, attenuation of immunosuppressive regulatory lymphocytes, and inhibition of tumor angiogenesis. IL-12 production via a gene-based approach, as compared with bolus administration of recombinant IL-12, is better suited to achieve desired results due to its pharmacokinetic and safety advantages.

The clinical development plan for GEN-1 in GBM is supported by preclinical studies in animal models. Encouraging efficacy benefits of GEN-1 added to an approved chemotherapy drug, BCNU, have been demonstrated in a mouse glioma model. Addition of a single dose of GEN-1 with BCNU (carmustine [bis-chlorethylnitrosourea]) significantly increased survival compared to BCNU treatment alone. The GEN-1 treatment administered alone or in combination with BCNU produced infiltration of CD4+ and CD8+ immune cells in treated tumors as compared with untreated tumors, demonstrating activation of the immune system. The safety and biodistribution studies in normal mice showed GEN-1 plasmid was primarily confined to brain tissue and minimally distributed (<0.0001%) in other tissues.

TheraSilenceTM in lung cancer

Lung cancer is the second most common cancer in both men and women and the leading cause of cancer death worldwide. Tumor angiogenesis is essential for the development and progression of lung cancer. Vascular endothelial growth factor receptor-2 (VEGFR-2) and its ligand (VEGF) are involved in multiple angiogenesis and cell proliferation pathways. VEGFR-2 and VEGF are vital for tumor growth, mediating many key processes, including endothelial cell proliferation, invasion, migration, and survival, as well as vessel permeability. The localization and high expression of VEGFR-2 in the endothelium make it an attractive target candidate for the TheraSilence platform. In a mouse lung tumor model, VEGFR-2 siRNA (short interfering RNA) was formulated with TheraSilence LNPs. Intravenous treatment resulted in a significant decrease in VEGFR-2 transcript and a significant reduction in tumors found in the lungs, as seen below.

VEGFR-2 transcripts in mouse lung tumor models

Tumors in mouse lung models


ThermoDox® in bladder cancer

Bladder cancer is the fourth most common cancer in men and 12th most common cancer in women. The annual incidence continues to increase with an estimated 77,000 new cases in 2016 in the United States. In about half of all cases, at diagnosis the cancer is limited to the inner wall of the bladder. In the other half, upon presentation it has already invaded the bladder wall, lymph nodes, or other organs. No effective drug for bladder cancer has been approved by the US FDA since BCG (bacillus Calmette-Guerin), which was approved in 1990.

A key difficulty in treating bladder cancer is delivering effective medicine to the bladder wall and muscle. In a recent study of ThermoDox in bladder models, it was demonstrated that warm water irrigation of the bladder can release high concentrations of doxorubicin throughout all layers of the bladder wall. These data were recently presented at the International Congress of Hyperthermic Oncology (ICHO) and may pave the way for future studies in patients with bladder cancer.