Cancer Therapy (anti-tumor) Vectors: Therapeutic Antibody Gene Enhances the Anti-Tumor Effect of Vaccinia Oncolytic Virotherapy
Bevacizumab, Genentech’s anti-angiogenesis drug Avastin®, seeks to inhibit the formation of blood vessels in the tumor, effectively “starving” the tumor and stunting its growth. However, many such antibodies cannot efficiently penetrate tumors, ultimately limiting their effectiveness even when patients are given extremely costly high doses. To overcome these limitations, Genelux scientists successfully designed vaccinia vectors to carry and over=express an engineered single-chain Avastin-like antibody (GLAF-1) directly to tumors, while simultaneously retaining its oncolytic potency (replication and tum or cell lysis).
The graph below shows the results of virotherapy with the two vectors (GLV-108 and GLV-109) as compared with the Genelux parent oncolytic virus GL-ONC1 not encoding GLAF-1, and control mice (no treatment) in pancreatic cancer xenografts. The vectors engineered to over-express GLAF-1 significantly enhanced therapeutic effects compared to the control mice, over Avastin therapy alone, and even resulted in enhanced therapeutic benefit over GL-ONC1 alone. This approach points to an exciting new therapeutic concept: tumor-specific, locally “manufactured” anti-cancer therapy in humans.
Imaging (Deep Tissue) Vectors Virotherapy with Companion Deep-Tissue PET Imaging in Pancreatic Cancer
While optical imaging modalities are best suited for visualization of surface or near-surface tumors, additional imaging capabilities are required for imaging tumors and metastases located deep within the body. Genelux scientists constructed a new recombinant vaccinia virus (GLV-1h153) encoding the human sodium iodide symporter (which enables radioiodine uptake into the tumor) to facilitate serial long-term imaging of virotherapy with PET.
Not only did GLV-1h153 result in radioiodine uptake within the tumor and facilitate imaging via PET, it actually enhanced tumor regression when compared to previously-documented viral therapy with GL-ONC1 or radiotherapy treatment alone. These results indicate that GLV-1h153 is a tumor-specific anti-cancer agent for the eventual treatment of human pancreatic cancer patients, and is suitable for deep tissue imaging (as well as optical) to monitor therapy.
Building GL-ONC1 and Beyond
Genelux Corporation’s genetically engineered vaccinia virus, GL-ONC1, was derived from the LIVP vaccinia strain by inserting three expression cassettes ruc-gfp (a fusion gene of Renilla luciferase and green fluorescent protein), LacZ (beta-galactosidase), and gusA (beta-glucuronidase) into F14.5L (located between F14L and F15L), thymidine kinase (TK), and hemagglutinin (HA) loci, respectively (See diagram below).
Disruption of these nonessential genes and expression of the foreign gene expression cassettes not only attenuates the virus, but also enhances its tumor-specific targeting. GL-ONC1 has been used in many of the company’s in vitro cytotoxicity studies, efficacy studies in animals, and is currently in Phase I/II clinical testing in human cancer patients.