The promise, challenge and evolution of cell and gene therapy

Cell and gene therapy treatments offer the hope of a cure for diseases that would otherwise result in a lifetime of debilitation or early mortality, says Colleen Floreck, Vice President of Marketing and Strategy, Cell and Gene Therapy, Catalent

Cell therapy immunology treatments, such as those driven by chimeric antigen receptor T (CAR-T) cells, reprogramme immune cells to attack leukemic B cells that are refractory to treatment.

Additionally, current late-stage gene therapy treatments use viral vectors to deliver genetic material to patients with rare diseases. Functional genes provide these patients with a significantly better quality of life.

This dire and often time-sensitive patient need, combined with the potential curative properties of these treatments, has propelled an already growing market.

Cell and gene therapeutics are entering the pipeline at an increasing pace with a double-digit compound annual growth rate (CAGR), derived in part to “Fast Track” designations accelerating agency approval timelines.

Marketed gene therapies include Spark Therapeutics’ Luxturna to treat congenital night blindness and Axexis’ Zolgensma for spinal muscular atrophy. Commercially available CAR-T products for B cell leukaemia include Novartis’ Kymriah, Gilead’s Yescarta and Kite Pharma’s Tecartus.

In 2019, the US FDA’s Commissioner of Food and Drugs, Scott Gottlieb, said that he expected 2020 to deliver more than 200 investigational new drug applications for cell and gene therapies per year … and that the agency would be approving up to 20 a year by 2025.1

Gene therapy

Of the viral vector types used by gene therapy innovators, adeno-associated viral (AAV) vectors have proven to be a safe vehicle to get genetic material into cells.

AAV genetic material does not incorporate into the host genome and maintains long-term expression (10–30 years) because of its episomal nature.

AAV production, however, is rather complex and challenging compared with traditional monoclonal antibody production, partly because of scalability challenges and non-standard expression systems.

Unlike traditional biologics, cell and gene therapy innovators do not have the luxury of years of standardised and regulatory approved manufacturing processes to onboard their drug targets as they move to a commercial-ready state.

These challenges, combined with the high growth rate of the market, are driving cell and gene therapy manufacturers to employ innovative development and manufacturing technologies to adapt to this accelerated clinical landscape.

These adaptations include process optimisation strategies, early supply chain planning, analytical development optimisation and capacity planning for commercial production to mitigate future demand.

Investors also look for therapeutic companies to have a commercial manufacturing plan in place, even during the early clinical development stages, which makes it critical that innovators secure manufacturing space as soon as their programme shows promise.

With such high demand in the market, combined with a complex manufacturing process and limited global expertise, innovators are pushing to book their suites now, ensuring access to scale-up capacity when ready.

Contract development and manufacturing organisations (CDMOs) are well suited to take on the risk of building capacity and developing efficient processes for late-stage manufacturing.

With multiple cell, viral types and treatment modalities across the cell and gene therapy market, CDMOs gain experience with a variety of equipment, techniques and processes.

Additionally, with expanded offerings in the supply of expensive starting materials such as plasmids, customers can feel confident that their supply chain is more secure and have the additional advantage of optimising the manufacturing process as early as plasmid production.

Dynamic changes in platform processes and scale are prevalent in gene therapy bioproduction as well. Many companies have moved or will move from cell factory based growth platforms to suspension bioreactors.

There have also been advances with the addition of nanofiltration to the process to make it more robust. It is this type of constant process evolution that requires developers to be open to all emerging ways to increase efficiency and scale … and ultimately generate more patient material and improve vector yields at a better cost.

Autologous CAR-T cell therapy

In autologous CAR-T cell therapy, the patient’s white blood cells (specifically cytotoxic T cells) are removed, isolated, purified, expanded, transfected using recombinant viral vectors and, ultimately, returned to the patient.

Patients often have a long history of cancer treatments and by the time cell therapy is recommended, they may be very ill. Expanding a sufficiently large pool of T cells that is healthy enough for reprogramming is a daunting task.

Although the first autologous cell therapy commercial products have shown tremendous clinical success, scaling-out these therapies while considering individual patient biologics and processes is an increasing challenge.

Like this story? Subscribe to Manufacturing Chemist magazine for the latest news, updates and expert-written articles from the global pharmaceutical and biopharma sectors. For more information click here.

As autologous cell therapies are patient-specific, a separate batch must be produced for each patient, limiting production standardisation across multiple patients.

The scale-out process is often complex and costly, requiring the concurrent handling of multiple batches while maintaining the need for patient-specific customisation.

This adds a significant risk profile to the manufacturing process. Close control of collection, shipping, storage and culture conditions is needed to avoid contamination with other patient batches.

Allogeneic CAR-T cell therapy

The alternative to bespoke CAR-T autologous cell therapy is to prepare and freeze CAR-T cells for off-the-shelf use. These cells are drawn from healthy donors and then delivered to ill patients; as such, the bottlenecks of variable cell activity and the stress of compressed preparation times are removed.

The use of allogeneic (non-patient, healthy donor) cells has many potential advantages compared with autologous (patient cells) approaches, including

  • the immediate availability of cryopreserved batches of CAR-T cells for patient treatment
  • possible standardisation of the cell product from healthy donors
  • available time for multiple CAR T cell modifications
  • redosing or combinations of CAR-T cells directed against different targets
  • decreased costs by using an industrialised process and, most exciting, reaching more treatment-indicated patients.2

However, there have been concerns with allogeneic cell therapy modalities in terms of potential immunogenicity and manufacturing at scale for this novel advanced modality.

Catalent’s Cell Therapy team is addressing the scale-up challenges and bottlenecks in allogeneic cell therapy production by implementing a unique Manufacturing by Design methodology, which creates a customised approach to each project.

It includes a detailed diagnosis of the client’s process, growth optimisation techniques, scalable development and manufacturing.

Additionally, innovation is ongoing within the cell therapy fill/finish platforms, moving towards a capacity of 1000 vials/batch and setting a new standard for commercially scalable allogeneic therapies.

Strategic partnerships with key advanced therapeutic companies, coupled with a strong commitment to grow and invest in innovative technologies, equipment and facilities, positions CDMOs such as Catalent as ideal partners for the clinical pipeline of cell and gene innovators.

References

  1. www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics.
  2. S. Depli, et al., “Off-the Shelf CAR-T Cells: Development and Challenges,” Nature Reviews 19, 185–199 (2020).

Companies