A perfect storm: Covid-19 viral vector manufacturing adds further burden to CAR-T development

Despite a slow return to normal, experts tell Adam Zamecnik that the impact of Covid-19 is still being felt across the CAR-T cell therapy industry.

Covid-19 viral vector vaccine manufacturing has placed additional pressure on the already stretched chimeric antigen receptor (CAR)-T cell therapy industry in terms of greater demand for key reagents, say experts. They have also seen shortages of other important materials like plastics that are part of production. Despite improvements in the industry, the pandemic continues to affect the sector’s development.

Labor shortages are adding further stress to CAR-T manufacturing, with some experts noting that the sector remains generally understaffed. This may be felt even more strongly by academic institutions, which have seen their talent move towards private players. These stresses have been compounded by the sector’s overall growth, experts say.

Viral vectors in hot demand

According to Romain de Rauville, vice president of Business Development at Exothera, a Belgian contract development and manufacturing company (CDMO) specializing in viral vector manufacturing for gene therapies and viral vaccines, there has been a tremendous increase in the demand for vaccine manufacturing capabilities since the beginning of the pandemic on top of an already overstretched industry. Rauville specifically notes that this increase began in Q2 2020.

Likewise, according to Fatma Senkensen, executive director of Marketing and Commercial Development, Cell and Gene at Lonza, the company received increased demand for viral vectors during the pandemic, including in vaccines. Additionally, the pandemic further fueled the supply crunch felt by the industry, she says.

Players in the CAR-T space and in vaccine production are fighting for the capabilities of viral vector producers, particularly since these capacities are largely the same for adenoviral, lentiviral, and adeno-associated viral vector production, says Rauville.

Adeno-associated viral vectors are used in the production of AstraZeneca’s and Johnson & Johnson’s Covid-19 vaccines, as well as for Russia’s Sputnik-V and others. Lentiviral vectors are often used in CAR-T production.

The demand for viral vectors used for Covid-19 vaccines has a sense of urgency, says Rauville. While the CDMO selection process can take months, Rauville has encountered companies wanting to start work on their Covid-19 programs in a matter of several weeks. From the perspective of a CDMO, Rauville cites the need for flexibility, which allows companies to quickly shift their viral vector production.

While such pressure has reduced since the height of the pandemic, viral vector supply will likely take longer to recover. Indeed, according to Matthew Durdy, CEO of Cell and Gene Therapy Catapult, the sector saw an acute period of widespread material shortages as result of the vaccine production drive about one year ago, and the sector has likely gone past this peak. However, Rauville says the demand for viral vectors in Covid-19 vaccines remains, noting that the company just signed a yet-unannounced deal to supply vectors for producing a Covid-19 vaccine.

While the initial impact of the Covid-19-related production crunch is no longer imminent, Senkensen says she believes that there will be more planned and steady growth of demand for such vaccines. Lonza previously announced its manufacturing collaboration for Altimmune’s Covid-19 vaccine candidate in its Houston facility in March 2021.

That said, the impact of viral vector-based vaccines is less clear moving forward, given the availability of messenger ribonucleic acid (mRNA)-based vaccines, says Qasim Rafiq, PhD, associate professor in cell and gene therapy bioprocess engineering at University College London. Therefore, the impact of these vector-based vaccines is not as significant as it could have been, he adds.

Improvement forecasts still few years off

As such, improving the supply of viral vectors remains a major challenge post pandemic.

Rafiq says he could see an improvement in the supply of viral vectors occurring within the next two to three years, citing conversations he has had with those in the field.

Rafiq mentions companies being placed on three-year waiting lists for access to good manufacturing practice (GMP) viral vectors. Natalia Elizalde, PhD, business development director at VIVEBiotech, a CDMO specialising in lentiviral vector production, says there has been a clear increase in demand for viral vectors in the CAR-T sector. This has prompted the company to focus on expanding its capacities to meet such demand, she says.

Besides reagents, shortages due to Covid-19 have also affected the supply of recombinant cytokines needed for T cell expansion, according to Rauville and Patrick Hanley, PhD, director of the Cellular Therapy Program at the Children’s National Hospital in Washington DC. Specifically, the cytokine stock has been affected by wider shortages of plastics that are used in its production, he adds. The shortages of materials like plastics could last for the next 12 to 18 months, says Rafiq, citing conversations with vendors.

Labour shortages felt across the sector

Ultimately, there are too few workers skilled in operating the facilities used in CAR-T production, says Durdy. Although Hanley cites having a technician leave for Covid-19 vaccine development, among other factors, quantifying the impact of Covid-19 on CAR-T workforce shortages remains difficult. Growing the industry will require a scaling of the workforce, says Krishnendu Roy, PhD, director of the Marcus Center for Therapeutic Cell Characterisation and Manufacturing at Georgia Tech, Atlanta.

This shortage is perhaps more pronounced in academic players. Juliana Dias Alves Pinto, head of GMP CAR-T production at the Centre for Cell, Gene & Tissue Therapeutics at the Royal Free Hospital in London, UK, saw her team reduced to half due to staff leaving for other opportunities. Seeing increased investment in the CAR-T space resulted in greater competition for talent, particularly by commercial players, says Dr Jerome Ritz, executive director of the Connell-O’Reilly Cell Manipulation Core Facility at the Dana-Farber Cancer Institute.

Main image credit: Lonza