Are stable producer cells the future of viral vector manufacturing and when will allogeneic cell therapy take hold?

The publication, based on data generated from a questionnaire with 150 industry representatives, explores the challenges and solutions facing cell and gene therapy (CGT) companies over the next few years.

The top six trends identified in the CRB survey​​ were:

• Multiple modalities are coming in two years.
• Gene therapy will grow by 20% yearly through 2025.
• Facility optimization and new processes are in the crosshairs.
• Turnkey project delivery is hot, despite concerns about procurement risk.
• Genetically-modified cell therapy will rely on CMO/CDMOs, due to internal capacity issues.
• Better regulatory compliance depends on closed bioprocessing.

We got the inside track from Noel Maestre, director of SlateXpace, a CRB solution focused on suite-based manufacturing platforms for the Advanced Therapy Medicinal Products (ATMP) and Peter Walters, CRB’s director of ATMP, on how the CGT landscape is likely to develop in the short-term.

In a recent report, the MIT’s Center for Biomedical Innovation projected​​ that around 500,000 patients will have been treated with 40-60 approved gene therapies by 2030.

“Going from the current scenario whereby only a few gene therapies are approved to 60 launches in a decade would represent an extraordinary leap forward and would dramatically change how medicine is actually perceived,”​ said Maestre.

But as regards CGT production today, especially autologous cell therapy (ACT) work, he said that while the science exists the technology - process equipment, facility design and automation platforms - is really still trying to catch up, endeavoring to address a sector that has exploded in the past five years, he commented.

Looking ahead at the CGT landscape over the next few years, he expects a significant amount of change. “The science is evolving – we see the industry moving away from old cell lines to new cell lines or moving away from viral vectors altogether and using cleavage enzymes as a gene editing tool.”​

A new host cell line – stable producer lines – is gaining momentum, he said.

“We are seeing the industry moving towards suspension cell culture from less than optimal cell lines, and then further going into producer cell lines.” ​

A full 65% of respondents to the CRB poll said they are developing or intend to develop this type of vector host cell, drawn by the potential for a less expensive, more scalable process. 

“Once the industry gets to the point where producer cell lines are more like a name brand, easier to pull off the shelf and use, it will be a much more cost-effective way to produce viral vectors.  ​

“But we are right on the cusp - a lot of companies are recognizing the opportunity and are investing the time and money into producing these. And we also see a lot of contract development and manufacturing organizations (CDMOs) producing their own cell lines in house and using those as a lure to [attract the clinical material work] of their clients,”​ said Walters.

Multiple modalities 

According to Maestre, and the CRB survey data backs him up, the product pipelines of companies operating in the CGT space are going to get more complex, for the next five years at least.

More than half of those polled indicated they expect to adopt a multimodal solution within the next two years, with flexibility, scalability, operational efficiency, and speed to market as the top drivers.

“Every company is going to be dealing with this dilemma of whether they build dedicated spaces for each of their different modalities, or whether they build highly flexible facilities that can allow them to accommodate whatever is coming next,”​ said Maestre.

He also sees a lot more companies wanting to integrate their supply chain, bringing a lot of manufacturing in-house whereas before they would have been reliant on a whole set of different CDMOs and manufacturers.

Project delivery is also where change is occurring.

“We are seeing the industry really moving away from the way projects were executed in the past into a much more integrated model; they are looking for turnkey facility delivery and they want turnaround to be faster. COVID-19 has only accentuated that, with project timelines compressed by 30-40%, and I don’t think that it is ever going back to the way it was – I think that is going to become the standard,”​ commented Maestre.

And another major trend over the next few years will be around the cost of therapies. “As they become more commonplace and there are more and more CGT licensed products, the costs will come down.”​

From autologous to allogeneic cell therapy

Projecting forward, Walters sees an eventual shift away from autologous to allogeneic cell therapy.

“As the technology continues to develop and the science continues to improve and new and better ways are found to use and leverage cells, we will see companies moving to a scalable allogeneic model, getting away from having to do that point-of-care, personalized tracking and more towards a classic manufacturing model that allows them to produce cells in advance in a way that they can be scaled up.”​

The idea, evidently, is to process cells for not one but dozens of patients at a time.

“We see the industry moving towards donated cells for allogeneic therapy and we are also seeing the beginnings of a shift to using stem cells that can be genetically modified and scaled up and differentiated to become T-Cells or NK cells. I don’t think industry has settled on a course yet but there are a lot of companies trying to find that pathway, trying to find the edge to move their manufacturing platform that way,”​ remarked Walters.

COVID-19 induced backlog

Right now, though, all facets of CGT manufacturing are under pressure from COVID-19 vaccine production, they said.

There is significant shortage of cleanroom manufacturing space to manufacture and develop the almost 1,200 CGT products in clinical trials currently.

“What we are seeing is that CDMOs have so much demand - they have 12-18 months of backlog in terms of contracts for product development – so they are building [new facilities] very rapidly.​

“As owner operator companies are stuck with that delay in getting their products into development, they are also developing a significant amount of manufacturing space on their own. But while both branches are building as fast as they can, it still isn’t enough.  ​

“We are constantly hearing from our clients that they are concerned about their supply chains and being able to secure their material. Right now, a lot of companies are moving towards a combination of using CDMOs and manufacturing in-house,” ​said Maestre.