Collaborative Research and Quality Control Supports Cell & Gene Therapy Development & Manufacturing

Featured Experts:

Jérôme Larghero, Director of the Department of Biotherapies and the MEARY Center for Cell and Gene Therapy in the Saint-Louis Hospital, AP-HP

Julien Textoris, Vice President of Global Medical Affairs, Immunoassays, and Host Response, bioMérieux

The landscape of advanced therapy medicinal products (ATMPs) continues to evolve rapidly, revolutionizing modern medicine to help provide additional treatment options for patients with rare diseases, cancers, and autoimmune disorders. In 2021, there were over 2,400 ongoing clinical trials for regenerative medicines worldwide. Quality control (QC) remains critical throughout the production process to ensure safe and consistent products for patient consumption.

In episode 8 of the EPR (European Pharmaceutical Review) podcast, experts Jérôme Larghero, Director of the Department of Biotherapies and the MEARY Center for Cell and Gene Therapy in the Saint-Louis Hospital, AP-HP, and Julien Textoris, Vice President of Global Medical Affairs, Immunoassays, and Host Response, at bioMérieux, discuss the role of collaboration among stakeholders in driving efficient and safe cell and gene therapy (CGT) development and why quality control can improve efficiencies in product development and delivery.

In episode 9 of the EPR (European Pharmaceutical Review) podcast, experts Jérôme Larghero and Julien Textoris continue their discussion on CGT and further explain why overcoming barriers in manufacturing and development are worth the challenges and what key areas are vital to consider for the future of the industry.

Effective collaboration among academic institutions and industry stakeholders is vital for the development and manufacturing of cell and gene therapies. As Jérôme Larghero explains, combining expertise supports research objectives that can lead to new developments in the sector. bioMérieux and the MEARY Center have been collaborating for several years to support growth in the CGT market.

The MEARY Center, dedicated to CGT manufacturing, runs projects to support both academic and industrial partners. The organization develops and optimizes the CGT manufacturing process throughout all three phases of clinical trials. “Our aim is not to be focused only on a cell type, or focused only on one disease, but we aim at addressing different diseases with different cell types and different approaches”, says Jérôme Larghero.

As a world leader in in-vitro diagnostics, bioMérieux provides innovative diagnostic solutions to help address many public health challenges and protect consumer health – including challenges in CGT manufacturing. As Julien Textoris details, having leadership positions in microbiology both for clinical and industrial applications provides manufacturing support for CGT development with reagents, IT solutions, advanced QC, and environmental monitoring tools to help support in-line product development. 

QC and safety testing during the manufacturing process must be addressed before a product is released for patient consumption. There are several challenges to consider throughout the development and manufacturing of advanced therapies, including the types of QC that should be performed for each product, how to choose the best QC methods, the timing of QC during the manufacturing process, to whom QC should be subcontracted, and how to fulfill regulatory requirements for new and evolving technologies. There are three main safety testing performed today in C&GT, these are sterility, mycoplasma and endotoxins.

It is important to understand that ATMPs and CGTs are not chemical drugs; they come from harvested and modified living cells, so the manufacturing and quality controls must be specific, especially for cellular attributes. “We all know that two healthy donors are different because their cells are different. At the end, we are supposed to have robust, reproducible processes, and much is based on how you will qualify your product and thus, which kind of quality control you will put in place to enter this drug into business and its reproducibility”, says Jérôme Larghero.

In addition to QC and safety testing, factors such as time-to-result, cost, and automation can greatly impact production time. With microbiological testing, obtaining results can take 7-10 days, and anywhere from 5-10 days are needed for in-process controls. “So, it's a long way. And it can be very difficult for us to have our patients treated between this month and waiting at the end to be injected with the particles”, explains Jérôme Larghero. However, if new technologies can be implemented to help reduce time-to-results, it could allow a very sick patient to be treated earlier.

It is important to consider what role QC may play for the patient and their perspective on the safety and efficacy of the treatments they receive. Because these cells are genetically modified, there is always a risk associated with gene therapies. It is critical to ensure that the manufacturing process is reproducible, robust, and fulfills all regulatory requirements. 

There has been a lot of discussion about the potential of creating allogeneic products, where cells are harvested from a healthy donor who is not the patient, in contrast to autologous products, where cells are taken from the sick patient. In addition, the five approved chimeric antigen receptor (CAR)-T cell therapies, none to date are allogeneic.

Research and development is underway to support the utilization of allogeneic CAR-T cells. Jérôme Larghero explains that allogeneic CAR-T cells are typically used for different applications than autologous. With autologous therapies, it’s expected that the CAR-T cells will cure the disease. With the allogeneic situation, the objective of the therapy is slightly different since there is a chance the patient may reject cells that are not their own.

Using allogeneic CAR-T cells makes it easier to produce multiple batches for many patients at once, so reproducibility easier to achieve. “This is much easier, you will be able to produce a lot of batches from one, two, or ten different healthy donors and you will be able to have your drug product on the shelf and immediately at disposition for the different patients”, says Jérôme Larghero. Although the QC process is very similar for production of allogeneic and autologous cell therapies, producing batches patient by patient requires more QC testing than producing larger batches at once. It’s expected to have some additional quality control testing in allogenic products like clinical relevant viruses (HIV, HCV, EBV etc)

When the autologous approach is used, it is also important to consider the timing in which the cells are harvested. “Of course, it is likely better to harvest the cells early in the development of the disease, rather than after one line, two lines, or six lines of chemotherapy and or radiotherapy”, Jérôme Larghero adds. The cells can be affected dramatically by the different regimes of chemotherapy.

Another key area of interest for many stakeholders looking to the future is whether the success of CAR-T cell therapies for hematological cancers can be used for solid tumors and cancer care. To date, there are five autologous CAR-T commercialized products for hematological cancers.

As Jérôme Larghero explains, although there has been a lot of research done in this field, there are still many hurdles to overcome. The first is identifying the different targets in tumor cells. The second issue, which may be the most important, is the difference between a solid tumor and its microenvironment, and a liquid tumor. “I would say that to date, the reason why there are not so encouraging results in the use of CAR-T for solid tumors is mainly due to this problem of microenvironment”, says Jérôme Larghero. These challenges may lead to isolating more specific targets or combining various immunotherapies such as TCR’s, CAR-T and checkpoint inhibitors. Current clinical trials underway include therapies for gastric, colon, pancreatic, breast, lung, melanoma, and glioblastoma cancers. 

More data is needed to evaluate the cost-effectiveness pertaining to the development and utilization of CAR-T cells globally. Reducing costs will be vital in deploying these treatments more widely in the future, although some countries do have reimbursement programs to assist with developmental costs.

Jérôme Larghero explains that his motivation in this industry is seeing the benefit for the patient. “I think it's fascinating to see all the interactions that interplay between all these therapeutic tools that that we have today…unfortunately CAR T doesn’t cure all patients, but it cures some patients who do not have any other possibility of treatment”, says Jérôme Larghero.

The future of the CGT industry is bright and may lead to CGTs being positioned earlier in the patient care pathway. There are many possibilities for fundamental and clinical research and innovation to support new developments in the field, such as allogeneic products and utilizing CAR-T cells in certain cancer treatments and diseases.