Our licensed gene therapy, CO-sTiRNA™, is a dual-action STAT3 inhibitor. STAT3 is a gene that drives tumor cell growth and anti-tumor immune suppression. CO-sTiRNA™ is a highly selective and targeted gene therapy that silences the activity of the STAT3 gene by way of RNA interference. CO-sTiRNA™ also stimulates TLR9 receptors to activate the body’s immune defense to recognize and kill cancer cells.

Cancer is caused by genetic mutations that result in the uncontrolled division and proliferation of abnormally functioning cells. The STAT3 gene plays a fundamental role in cell growth and division, cell movement and apoptosis in both tumor cells and tumor associated immune cells. Studies suggest that many cancers depend on the activity of STAT3 to survive and proliferate. The ability to selectively and temporarily silence STAT3 is highly desirable for certain cancer therapies.

The ability to selectively and temporarily silence STAT3 is highly desirable for certain cancer therapies.

We are working with Dr. Hua Yu and Dr. Marin Kortylewski at City of Hope. Dr. Yu is the Billy and Audrey L. Wilder Professor in Tumor Immunotherapy, Associate Chair/Professor in the Department of Immuno-Oncology, and Co-Leader of the Cancer Immunotherapeutics Program. Dr. Kortylewski is an Associate Professor in the Department of Immuno-Oncology. Drs. Yu and Kortylewski are both leading experts in the role of STAT3 in tumor angiogenesis and tumor immune evasion and in oligonucleotide-based cancer immunotherapies and developed our STAT3 inhibitor. The strategy to pursue STAT3 inhibition was developed based on seminal discoveries by Dr. Yu and her team defining the key role of STAT3 in cancer cell survival and immune tolerance, combined with pioneering work by Dr. Kortylewski and his team on STAT3 targeting using TLR9-targeted delivery of siRNA oligonucleotide therapeutics into immune cells.

Multiple studies, including those conducted at City of Hope, have validated STAT3 as a promising target in non-Hodgkin’s lymphoma. There is growing evidence linking B-cell non-Hodgkin lymphomas to persistent activation of STAT3. In pre-clinical testing at City of Hope, the STAT3 inhibitor has successfully reduced growth and metastasis of various cancers, including lymphoma, leukemia, and solid tumors including melanoma, and colon and bladder cancers. Pre-clinical studies in City of Hope laboratories demonstrated that intratumoral injection of CO-sTiRNA™ combined with radiation therapy, or RT, has proven to be efficacious in eradicating established tumors in pre-clinical models of human and mouse B-cell lymphoma. The therapeutic effect of CO-sTiRNA™ combined with RT likely resulted from a two-pronged effect, reducing survival signaling in lymphoma cells, as well as decreasing tolerogenic/proangiogenic effects of the tumor microenvironment post-RT.

Local administration of CO-sTiRNA™ with RT resulted in complete rejection of mouse syngeneic B-cell lymphoma and significant growth inhibition of xenotransplanted tumors. Thus, the combination of local radiation and intratumoral injection of CO-sTiRNA™ represents a novel approach to elicit an anti-tumor immune response in the host.