Medical Device Daily European Editor

Two German companies, Apceth (Munich) and Indivumed (Hamburg), have entered a collaboration in an attempt to prospectively stratify cancer patients according to the genetic signature of their tumors, prior to offering them tailored gene therapy treatment based on the administration of ex-vivo-amplified mesenchymal stem cells (MSCs) that have been modified to express a suicide gene.

Apceth is developing adult stem cell therapy and gene therapy treatments in a range of indications. It has entered a partnership with Indivumed to gain access to the latter firm's tumor biobank in order to validate a patient-selection strategy based on classifying epithelial tumors according to the presence of tissue-specific promoters controlling gene expression within the tumor.

"It's a very new therapeutic strategy. We have to make sure we select patients appropriately," Apceth co-founder and chief scientific officer Ralf Huss told Medical Device Daily. "It's very important to work with companies and pathologists who really know how to handle tissue."

Indivumed has adopted a highly distinctive approach to tumor biobanking. The company has a team of 20 who attend surgical procedures and collect fresh samples instantaneously, according to standardized protocols. That ensures that the gene expression and proteomics profiles of the tissues it is collecting accurately reflect the in vivo situation.

The company has agreements with nine hospitals, in Germany and the U.S., which account for fourteen surgical departments in all. "It's extremely expensive – that's why no one else is doing it," Indivumed CEO Hartmut Juhl told Medical Device Daily.

The development of drug-function-related predictive biomarkers is now a fast-growing area, Juhl said, even if the development of prognostic disease biomarkers continues to lag, due to the heterogeneity of disease. However, the development of the whole field has not been helped by the widely divergent protocols used for tissue collection. "This inconsistency is remarkable," he said.

The aim of Apceth's approach is to sensitize tumor cells to the antiviral prodrug ganciclovir, by introducing a construct containing the gene encoding the Herpes simplex virus (HSV) enzyme thymidine kinase (tk), under the control of a promoter that is already active within the tumor. "We bring them in as Trojan horses," Huss said.

The strategy exploits the natural homing of MSCs to the tumor microenvironment, where the cells ordinarily contribute to tumor angiogenesis or new blood vessel formation. Expression of the HSV-tk gene leads to production of a cytotoxic metabolite, however, which arrests the cell cycle and induces apoptosis.

The cell-killing effect within the tumor microenvironment is further amplified by a well-known bystander effect. Cells do not need to take up and express the HSV-tk gene in order to be killed, as phosphorylated ganciclovir molecules can move into neighboring cells across gap junctions and mediate their toxic effects.

Apceth has already validated the approach in several mouse models of cancer, including metastatic breast cancer, metastatic colorectal cancer, hepatocellular carcinoma and pancreatic cancer. "It's attacking an overall principle of tumor growth, it's targeting tumor angiogenesis and the tumor microenvironment," Huss said.

It has developed several different transgenes, each comprising the HSV-tk gene under the control of a different promoter. "Currently we have a selection of three to four potential promoter candidates," Huss said. It now aims to develop a platform technology that would enable routine testing of patient tissues in order to match their tumor profiles with the correct form of the stem cell therapy.

In parallel with the biomarker development initiative, it is also gearing up for its first clinical trials. "Our first indication is pancreatic cancer," Huss said. "We will start a first phase I/II clinical trial next year – in 2013. We are currently talking to the regulator about the trial design." That first study will involve just one of the constructs. "We have a pretty good hunch about what we will most likely select," Huss said.

Apceth is backed by the deep-pocketed Strungmann brothers, Thomas and Andreas, who are among the most prominent life sciences investors in Germany. The company already has one program in the clinic, an autologous MSC therapy, which is undergoing a phase I/II trial in patients with advanced peripheral arterial occlusive disease (pAOD) who have already received angioplasty therapy.

The underlying rationale is that the MSCs would act as regenerative therapy by providing a host of growth factors and signal molecules that would promote new blood vessel formation and reduce local inflammation. Apceth has developed a GMP process, which, it says, provides it with pharmaceutical-grade, well-characterized cell populations. That study is due to report either later this year or early next year.

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