Therapeutic viruses to treat cancer and gene defects

Oncolytic virotherapy is based on the ability of viruses to selectively infect and replicate in cancer cells, while sparing healthy tissue. Productive virus replication induces lytic cell death, the release of cancer-specific antigens and an inflammatory response in the immune-suppressed tumor microenvironment which is then potentiated into a multi-faceted activation of the immune system and a systemic tumor vaccination. It is also worth noting that oncolytic virotherapy does not only provide high levels of therapeutic efficiency, but also results in significantly fewer side effects compared to conventional anti-tumor therapeutics.

While oncolytic virotherapy is based on the tumor-selective infection and replication of certain viruses, virus-based gene therapy relies on the ability of viruses to deliver or even permanently integrate genetic information into their target cells. This virus-mediated gene expression then results in reduced disease burden or even complete remission in patients suffering from genetic disorders.

Strategies to personalize oncolytic virotherapy as part of precision medicine approaches strongly depend on genetic engineering of viral genomes resulting in therapeutic viruses especially tailored to an individual‘s tumor phenotype. Such therapeutic viruses for instance express surface proteins that only bind to receptors selectively present on an individual’s tumor cells or which deliver a specific therapeutic payload leading to the targeted destruction of already therapy-resistant malignancies. By combining those engineered oncolytic viruses with other treatment options such as therapeutic antibodies, cell- or radiotherapy, individually tailored treatment regimens with higher efficiency are generated.

Despite their obvious potential as efficient therapeutic modality, currently only eight virus-based therapies have been approved by the responsible regulatory agency in America, the FDA and its European counterpart, the EMA. Among those eight approved virus therapies, only one is an oncolytic virus, whereas 94 registered clinical trials were on-going in February 2024 to obtain approval for virus-based cancer therapy, making it clear that compared to other anti-cancer treatments such as small molecules or therapeutic antibodies, the successful clinical translation of virus-based cancer therapies is still in its infancy.

While this lack in clinically approved oncolytic viruses partly originates from their more complex structure and mode of action compared to conventional cancer therapeutics  it also illustrates that further biotechnological research spanning the entire pharmaceutical value chain from early to late stage development is required to path the successful transition of (oncolytic) viro-science into the clinic.

This is precisely where the state of Baden-Württemberg's funding to establish a novel Fraunhofer IGB branch in Biberach an der Riß comes in, as this newly founded research unit focuses on the biotechnological development of virus-based therapeutics with a focus on virus, cell, and process technologies. The set-up and launch of the novel facility in Biberach was significantly supported by the expertise and existing infrastructures at the Fraunhofer IGB headquarter in Stuttgart.

The virus technology group focuses mainly on molecular virus engineering. By introducing targeted modifications into viral genomes, efficiency and activity of therapeutic viruses and viral vectors will be increased. An essential starting point of our current activities here was the previously developed proprietary herpes simplex virus 1 (HSV-1)-based TheraVision platform. While TheraVision was designed as a modular vector technology for the production and testing of viruses for tumor therapy, its particular benefit arises from its modularity, which allows the rapid genetic manipulation of the underlying complex herpes virus.

Based on those features, we recently developed so-called reporter viruses which express fluorescent proteins. Once their target cells become infected expression of those fluorescent proteins then allows to monitor viral replication kinetics in real-time.

Next to HSV-1-based oncolytic viruses, other therapeutically relevant vector systems, such as vesicular stomatitis virus and adenovirus, are also established in our laboratories. By using those various viral vector systems, we are planning to comprehensively assess structure-function relationships of the underlying virus species to gain insights into their therapeutic safety, specificity, efficacy, and stability.

Research activities in the virus technology group such as fluorescent reporter viruses will also be utilized within the cell technology group as part of cell line engineering, a particular focus of our work. Targeted cell line engineering aims to modify common production cells to increase the yield of functional viruses for therapeutic use, as in contrast to conventional vaccinations to prevent infectious diseases, treatment doses for immuno-oncology are much higher which limits their broader therapeutic roll out. Innovative methods such as CRISPR-CAS technology which enable the modification of cell metabolism, apoptosis, cell division or the antiviral innate immune response will be used to make production cell lines more resistant to virus-induced stress responses. Bespoke fluorescent viruses will allow here a direct at-line monitoring of the improved production capacity of CRISPR-CAS modified cell lines.

Last, our reporter viruses can also be used for preclinical efficiency testing to analyze replication kinetics and tissue penetration in complex tumor models. Such patient-derived models can also be utilized to dissect the differential or synergistic anti-tumor and immune-activating effects of the TheraVision virus compared to other viral systems such as vesicular stomatitis viruses and adenoviruses. This makes it possible to identify factors that influence the individual efficacy of oncolytic virotherapy.

The process technology group complements the scientific research conducted within the virus and cell technology divisions by providing expertise in process development, analysis and scaling. In downstream processing, chromatographic bio-separation processes to minimize infectious titre losses throughout virus purification or cryopreservation and formulation studies in order to achieve maximum product stability are developed.