Combining the experimental therapy MDNA55 with anti-cancer interferons (IFNs) can effectively kill cancer cells and extend the survival of mice with metastatic ovarian cancer, new research results show.
The study, “Combination immunotherapy with IL-4- Pseudomonas exotoxin and IFN-α and IFN-γ mediate antitumor effects in vitro and in a mouse model of human ovarian cancer,” was published in the journal Immunotherapy.
MDNA55 is a fusion protein being developed by Medicenna Therapeutics that contains a modified interleukin-4 protein fused to a toxin from the bacteria Pseudomonas (IL-4-PE). It specifically targets the IL-4 receptor, a protein that is over-produced in 20 different cancer types, including ovarian cancer. Once IL4-PE binds to IL-4R, it is taken up by the cells, thereby stopping protein synthesis and inducing cell death.
IFNs are molecules with a well-known role in cell cycle and cellular proliferation, as well as in antiviral and antibacterial responses. Despite the current use of IFN-alpha subtypes in the treatment of hairy cell leukemia and melanoma, neither IFN-alpha nor IFN-gamma subtypes are used to treat patients with ovarian cancer. However, they have been suggested to limit toxicity and boost the efficacy of standard chemotherapies in these patients. Also, combining therapies may lower the cancer’s potential to mutate and become treatment-resistant.
Adding IFNs (both alpha and gamma subtypes) to MDNA55 can boost the ability to kill human cancer cells compared with each of these therapies alone, according to researchers from different departments of the National Institutes of Health and the U.S. Food and Drug Administration (FDA)’s Center for Biologics Evaluation & Research.
Using an experimental mouse model, the team found that the combination strategy had the potential to induce complete responses, or complete cancer disappearance, as well as to extend the animals’ lifespan without damaging vital organs or lowering body weight.
At the molecular level, ovarian cancer cells treated with MDNA55 and chemotherapy showed less proliferation, significant activation of the IFN and IL-4 signaling pathways, as well as subsequent activation of key proteins — namely Caspase-3 and -7 — in apoptosis (programmed cell death, as opposed to death caused by injury), and PARP.
Additional experiments revealed that the cancer cell death is dependent on IFN, but not on IL-4 signaling, as revealed via blockage of their pathways with FDA-approved treatments ruxolitinib (marketed as Jakavi by Incyte in the U.S.) and tofacitinib, respectively. This indicates that the anti-cancer effect of MDNA55 and IFNs is triggered through distinct and complementary mechanistic pathways, according to the scientists.
“These data suggest that this novel combination could provide a unique approach to treating ovarian cancer,” the researchers wrote. “Additional studies are planned to support a Phase  clinical trial with IFNs and IL-4-[Pseudomonas exotoxin].”
MDNA55 has been used to treat more than 130 patients in several clinical trials, and showed a favorable safety profile and anti-tumor activity in patients with recurrent glioblastoma, according to Medicenna.
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