Gene and cell therapies: making manufacturing work

Gene and cell therapies are two of the fastest emerging areas of medicine. Comprising techniques such as gene editing and next-generation immunotherapy, they could treat – or even cure – a broad range of previously untreatable diseases.

To understand their potential, we only need think of the examples that have already been approved. Kymriah, a treatment for B-cell acute lymphoblastic leukemia, involves genetically altering the patient’s T-cells to attack leukemia cells. Provenge, a therapeutic vaccine for prostate cancer, reprograms the patient’s immune system. Luxturna, the first in vivo therapy approved by the US Food and Drug Administration (FDA), treats patients with a form of congenital blindness.

While this is a challenging field – not least because of funding issues – the potential is immense and researchers are exploring the possibilities across a vast range of protocols and technologies. According to the American Society of Gene and Cell Therapy, there are currently more than 1,000 different types of gene therapy in clinical trials and more than 8,000 active, or actively recruiting, clinical trials for cell therapies.

The appeal is obvious: rather than simply addressing the symptoms of a disease, these are personalised treatments that tackle the actual disease etiology.

“I think cell and gene therapies will have great importance in the future,” says Dr Pascale Bouillé, CEO of Flash Therapeutics. “They are used for many diseases from genetic diseases to cancer to metabolic diseases to cardiovascular diseases to brain diseases.”

A brand new gene therapy company, Flash Therapeutics was formed in May from the merger of Vectalys and FlashCell. Vectalys, a Toulouse-based biotech, was founded in 2005 to produce lentiviral solutions for gene delivery. FlashCell, its spinout startup company, was launched just two years ago to develop ribonucleic acid (RNA) carriers.

The merger, explains Bouillé, came about as a result of overlaps between the companies’ objectives. In short, FlashCell’s partners required the kind of manufacturing expertise offered by Vectalys.

“Following the creation of Flash Therapeutics, our biotech and pharmaceutical partners often asked us about the manufacturing,” she says. “The technologies are really good but you also need manufacturing capabilities to develop the best product. So we realised that both activities are linked even if they required very different know-how, skills and funding.”

Flash Therapeutics, then, has a dual focus. Firstly, it develops novel RNA therapeutics based on its proprietary LentiFlash technology. Secondly, it offers contract development and manufacturing support for clients working on lentivirally-delivered therapies.

“A lot of companies are looking for manufacturers of lentiviral vectors, but they are not only looking for manufacturers, they are looking for experts that can support product development from research to GMP,” says Bouillé. “Since pharmaceutical companies were not implicated in cell development from the beginning – all the work was done by academic institutions and biotech companies – they now need to work with experts to speed up their product development.”

To give some background, lentiviral vectors are used within cell therapy to deliver genetic material into the target cells’ genome. The lentivirus family (which includes HIV) replicates quickly within the human body – during an infection, the virus attaches to a cell and injects viral material into its cytoplasm and nucleus. The host cell, now integrated with the foreign DNA, will begin to express viral proteins and new viruses.

In the 1990s, scientists realised this mechanism could be exploited to deliver specific genes into the cell. Lentiviral vectors have since been used across a number of experimental applications, and the technology has grown much safer and more effective.

In August 2017, researchers arrived at an important landmark – the approval of Kymriah. The first in a new class of treatments known as CAR-T therapies, Kymriah uses lentiviral vectors to modify the patient’s immune cells. It could pave the way for many others of its kind.

Although Flash Therapeutics (as Vectalys) has a long history of developing ‘standard’ lentiviral solutions, its LentiFlash technology takes a different approach. With a conventional lentiviral tool, the transferred genetic material is integrated into the target cells, leading to stable expression of the proteins. With LentiFlash, integration does not occur and the expression is transient.

This overcomes some of the safety concerns associated with integrative lentiviral particles. Plus, it means the tools can be used for an altogether different purpose. While integrative lentiviral vectors are used to treat cancers and certain genetic diseases, LentiFlash technology is suitable for gene editing and other advanced therapeutic approaches.

“For some genetic diseases, integrative lentivirus-based technology is useful because we introduce functional genes into the genome of patients and then obtain a stable expression, but there are times when stable delivery is not a good approach,” says Bouillé. “In 2010 we decided to develop a non-integrative technology, keeping all the innovative properties from the viral system and its ability to easily enter cells. The technology is the same in terms of delivery systems – we have a lentiviral particle – but inside the particles the genetic machinery is completely different and the technologies are dedicated to different applications.”

Currently, Flash Therapeutics is using its LentiFlash technology to develop therapeutics for blood and liver diseases. This is just the tip of the iceberg, though, and it plans to team up with other biotech companies to develop RNA therapies in other disease areas.

On the manufacturing side, the company is working to expand its lentiviral development and production business. Next year, it will open a new good manufacturing practice (GMP) facility at the Hospital Saint-Louis, Lariboisière, Fernand Vidal in Paris. Under a recently signed three-year partnership, it will use the facility to develop gene and cell therapeutics.

“Manufacturing technology has been our job for 13 years now and clearly we have a great expertise and experience in lentiviral vector manufacturing – we’ve produced more than 4,000 batches,” says Bouillé. “Our facility will deliver GMP batches of both lentiviral vectors and LentiFlash tools, and with our expertise we can support customers from drug discovery to the clinic.”

She adds that, as gene and cell therapies become more prevalent, there will be a growing need for lentiviral manufacturing technology and expertise. Flash Therapeutics hopes to play a key role in the process, helping its clients develop and commercialise new therapies in hard-to-treat diseases.

Equally, it wants to demonstrate the merits of LentiFlash, ultimately using the technology across a wide range of applications.

“When we use integrative systems, we then provide genetically modified organisms, which can have secondary effects due to the stable integration into the genome,” she explains. “We want to show that developing a non-integrative system can add more value to these therapeutic approaches. Biomanufacturing is really important to meet that objective.”