Genome Editing and Gene Therapy

Gene therapy has been a scientific and medical goal since the early days of molecular biology. However, only recently have advances in the understanding of safety and efficacy of the viral vectors used to deliver genes for therapeutic purposes enabled the promise to become a reality. As the technology has improved, there has been a surge in efforts to use gene therapy to address some of the most challenging diseases.

San Diego-based biotech company Tocagen has a vision of a world in which people don’t die of cancer. To achieve this goal, they are currently investigating a potential therapy to selectively deliver therapeutic genes into cancer cells. The gene carried by their lead product into cancer cells by a novel virus platform (gamma Retroviral Replicating Vector, RRV) is designed to produce a protein that converts an orally administered pro-drug into a potentially effective anti-cancer drug selectively within the virus-infected cell. This results in the activation of the immune system against the cancer by multiple mechanisms.

Tocagen’s lead product, which has recently received Breakthrough Therapy Designation from U.S. FDA for the treatment of recurrent high grade glioma (HGG) and Priority Medicines (PRIME) designation from the European Medicines Agency for the treatment of HGG, involves two discrete steps.  First, an investigational virus called Toca 511, which carries a therapeutic gene is injected into the residual tumor in the resection cavity wall immediately following surgical resection, or administered intravenously to patients with metastatic cancer. The virus is designed to integrate into the DNA of dividing cancer cells, which then serve as “factories“ for producing additional viruses. These new virus particles are then designed to spread to neighboring cancer cells, repeating the process and enabling long-term presence of the  therapeutic gene within the tumor. In the second step, patients take an investigational oral medication called Toca FC, which is designed to be activated only within infected cancer cells by expression of the therapeutic gene. 

After developing a production process in-house,  Tocagen needed a leader in the contract manufacturing of viral vaccines and gene therapy drug products to help them turn its innovative science into a viable, scalable approach that could potentially benefit many patients.  Manufacturing viruses for clinical trial supply and potentially commercial supply requires the ability to robustly scale production beyond what is required for earlier stages of clinical research.

“We wanted to work with scientists who were at the cutting edge of their field, who were committed to developing this therapy with us,” says Harry Gruber, president of science and innovation at Tocagen. MilliporeSigma met all of these requirements.

Harry Gruber , a medical doctor, who had worked with some of the original founders of the Carlsbad site earlier in his career. He therefore had a lot of confidence in their scientific ability and integrity.

1. Open and honest communication

2. Develop an understanding of each other’s needs, capabilities, and vision for success

3. Ensure that all of the necessary resources are available to sustain the partnership in the long term

4. Commit to constant communication between all levels of the companies including executives so that everyone is on-board with the partnership vision

5. Be willing to share your success story internally and externally

As a contract manufacturing organization, MilliporeSigma's site in Carlsbad produces viral vectors for use in gene therapy or gene-modified cell therapeutics for clinical investigation. MilliporeSigma had already had experience with a number of different viruses and viral vectors and had become an expert in these areas, so Tocagen chose MilliporeSigma to begin manufacturing the virus at a large scale. 

Tocagen has so far used the virus in three Phase 1 clinical studies and an ongoing Phase 3 trial. Of note, in those Phase 1 studies with human patients, they observed a favorable safety profile as well as  evidence of potential drug activity. Some of the data, initially reported in Science Translational Medicine, showed that multiple patients with recurrent brain cancer in the higher-dosage groups had durable complete tumor responses lasting multiple years . Based on these and other results, Tocagen is now conducting a pivotal Phase 3 trial and evaluating the treatment in patients with a wider range of tumor types. 

Asha Das is a medical doctor and the Senior Vice President and Chief Medical Officer at Tocagen. Her goal is to bring effective drugs to patients as quickly as possible. Her team writes protocols, conducts clinical studies, evaluates data, writes and submits publications – all of which are important to advance new medicines. 

Tocagen's and MilliporeSigma's relationship is based on a shared vision of an efficient gene therapy manufacturing platform that can make these therapeutics available to patients around the world. Their relationship serves as an example: Tocagen, with a novel platform for cancer immunotherapy and MilliporeSigma, with a deep expertise and long history in gene therapy and clinical trial manufacturing. For example, the teams have collaborated on many aspects of manufacturing including process optimization, automation, scaling, and validation planning. Together, the teams have successfully manufactured at clinical scale and are gearing up towards commercial supply.  The MilliporeSigma site was recently audited by both the FDA and EMA – a regulatory milestone that benefits both companies in their shared vision.

Building our capabilities and capacity in gene and cell therapy manufacturing is an investment in the future – and many companies that are developing these therapies might be able to benefit from it. Geographical proximity has certainly helped the two companies but was not a prerequisite for establishing a close relationship.