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Cancer Immunotherapy Firm Apeiron Poised to Move siRNA Therapy into Phase I Trial

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NEW YORK (GenomeWeb) – Austrian biotech firm Apeiron Biologics is putting the final touches on preparations to initiate a Phase I trial of a cancer immunotherapy that involves the ex vivo treatment of patients' white blood cells with siRNAs to boost their ability to kill tumor cells.

According to Apeiron CEO Hans Loibner, the company has already received approval from the US Food and Drug Administration for the study and is in the process of finalizing the trial's details with collaborators at Wake Forest University, where it will run. He said he expects the first patient to be treated within the next two months.

The treatment, dubbed APN401, is an adaptive cell therapy (ACT) comprising autologous peripheral blood mononuclear cells that have been transfected with siRNAs targeting a gene involved in adaptive immunity.

The open-label, dose-escalating Phase I study is designed to enroll up to 22 individuals with melanoma, pancreatic cancer, renal cell cancer, and other solid tumors who have failed previous therapy. Study participants will be treated with infusions of APN401 every 14 days for three courses.

Primary objectives of the trial are the determination of safety and the maximum tolerated dose of APN401, as well as the effects of treatment on immune responses. Secondary endpoints include clinical responses and survival.

Although the study is small, Loibner said that the experimental nature of APN401 has prompted regulators to require stringent monitoring of each treated patient before the next is dosed. As such, the trial is expected to take up to two years to complete.

However, he said that Apeiron may release preliminary study data prior to completing the Phase I should they be compelling.

Apeiron was founded in 2006 to develop treatments for cancer and related diseases based on the work of Josef Penninger, a researcher at the University of Vienna and director of the Institute of Molecular Biology of the Austrian Academy of Sciences.

Part of that work centers around the use of a patient's immune system to kill tumor cells, an approach that has already yielded one commercialized product in Dendreon's dendritic cell vaccine Provenge for prostate cancer.

ACT is another approach to cancer immunotherapy, but has thus far had limited success in solid cancers, in part due to immune evasion by tumors and poor functioning of the transferred cells. At the same time, efforts to genetically alter the cells to boost their potency carries risks like insertional mutagenesis.

Previously, while a researcher at the University of Toronto, Penninger and his team demonstrated that casitas B-lineage lymphoma proto-oncogene b (Clb-b), a ubiquitin E3 ligase, plays a key role in adaptive immunity, regulating activation thresholds in mature lymphocytes. Others, meantime, have shown that its loss triggers autoimmune susceptibility in animals, and that variations within the Clb-b gene are associated with multiple sclerosis in humans.

Additional work by Penninger and others has established a role for Clb-b in the induction and maintenance of peripheral T cell tolerance; demonstrated that Clb-b-deficient mice are less susceptible to both induced and spontaneous tumor formation in a range of cancers; and showed that Clb-b deficiency makes CD8+ T cells resistant to tumor-related immunosuppression.

On these and other data, Apeiron acquired the rights to Penninger's discoveries and began exploring whether inhibition of Clb-b in T cells could boost their efficacy in ACT. In 2012, the company and its collaborators published data showing the promise of this approach in a mouse model of melanoma.

In that study, polyclonal CD8+ cells were treated ex vivo with siRNAs targeting the ubiquitin E3 ligase and then introduced into the animals, resulting in significantly delayed tumor growth and increased survival. Moreover, the addition of the siRNA-treated T cells to a dendritic cell vaccine resulted in enhanced anti-tumor activity without autoimmunity induction.

Now, after optimizing the siRNAs and establishing a process for their clinical use, Apeiron is poised to begin testing it in humans.

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