✕
☰

From start to finish: Planning cell and & gene therapy in Europe

by

BioIVT’s Trevor Smith, MS, MBA, product manager, immune cells, describes necessary considerations when preparing to manufacture a cell or gene therapy, from starting materials to safety endpoints.

Key insights:

With more than a decade of success driven primarily by chimeric antigen receptor (CAR) T cell endpoints, the field of cell & gene therapy is seeing unprecedented growth globally. Europe has been positioning itself to facilitate the development of advanced therapeutics, recently courting Bristol Myers Squibb (BMS) to construct its CAR T cell therapy production centre in Leiden Bio Science Park in the Netherlands. To keep pace with the industry, developers in Europe would do well to consider the supply chain for their starting materials as well as the safety and efficacy of the final therapeutic product.

Choosing a relevant starting provider

The quality of cell & gene therapy starting materials, such as leukapheresis products and purified immune cell subsets, reliably determines the success of generating an advanced therapy – whether it is in the research, development, or clinical manufacturing phase. Therefore, it is recommended that sponsors choose an experienced starting material provider with a strong reputation for quality. Ideally the chosen provider will have a GMP-compliant product line because it demonstrates not only the quality of their research-grade products, but also a firm understanding of quality and regulatory oversight as it relates to customers’ clinical requirements. A GMP portfolio also guarantees an ability to scale with allogeneic therapy developers, as there is no need to transition from one provider to another when entering clinical trials.

The provider also needs to have access to a broad, diverse group of donors to test the limits of an advanced therapy production process and guarantee a reliable supply of specific types of donors for a single study. For example, autologous therapy developers are beholden to the age, HLA-type, and physical characteristics of the patient being treated for starting material. Their research and development programs should therefore test as many permutations of the above as possible to assure a robust manufacturing process to maximise patient access. Further, allogeneic therapy developers often identify characteristics of an “ideal” donor for their product’s starting material. As additional inclusion and exclusion criteria are added, such as those listed above plus exposure to certain pathogens such as cytomegalovirus, a starting material provider’s donor pools may quickly shrink from tens of thousands to dozens of eligible donors. To avoid delay in bringing therapies to market, therapy developers should articulate their ideal donor demographics upfront and work with providers who have characterised their donors to a level that can accommodate their customers’ needs.

The criticality of safety endpoints

While approved cell & gene therapies on market have demonstrated their efficacy, safety profiles remain a critical consideration. Potential adverse reactions such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, off-target effects, and other complications remain areas of focus for therapy developers. Other, rare complications such as CAR-transduced B cell leukaemia cells – wherein a patient’s leukaemia cells erroneously transform and express CARs – further emphasise the criticality of safety endpoints. Accordingly, bioanalysis has become an important aspect of advanced therapeutic development programs.

Traditionally, bioanalysis for cell & gene therapy at the pre-clinical level is performed through in vivo studies that test biologically relevant dose levels, safety in relation to said dose levels, and full characterisation of potential adverse effects including onset and duration. qPCR analysis is also performed on tissue to assess distribution, persistence, and any presence of the therapy throughout the body. These in vivo model tests are significantly more complex in cell & gene therapies than traditional therapies and often extend for more than a year to cover 28-day, 6-month, and 9-month timepoints for toxicology studies. These animal-based bioassays are often the most relevant to clinical response, but cell-based bioassays are generally regarded as most suitable for potency determination due to their lower variability. Further, ethical concerns may lead manufacturers to limit in vivo studies where possible.

In vitro bioanalysis studies characterise the therapy at a more granular level. Tests range from standard cell viability and count vial flow cytometry to functional assays such as cytotoxicity or cell killing evaluation of a therapeutic product against target cells. Cytokine release of cell therapies via ELISA can also be used to ensure the correct response is being had to the target and for what duration that response persists. For cell therapies, transduction efficiency via qPCR and expression of the surface molecules (e.g. CARs) via flow cytometry give insights into the requirements for lentiviral and/or retroviral vector demand. Single-cell “-omics” testing has grown in importance, as researchers are starting to see no two cells are exactly alike. Traditional “bulk” assays of multi-cell populations provide the average of the population but miss evaluating the features of individual cells as seen in single-cell RNA-seq studies. Further, more advanced cell therapies, especially for gene-editing based cell therapies, may require next-generation sequencing approaches.

For these and other assays, predevelopment preparation, method development, optimisation, and method transfer all add to the timeline for bringing a therapy to market. While Contract Testing Organisations and Contract Research Organisations can be leveraged, the explosive growth of cell & gene therapies in development has created a strain on these services – which were further burdened during the COVID-19 pandemic. Therapy developers with their own internal analytics capabilities can save time by working with starting material suppliers who can isolate purified populations of immune cells to custom specifications to maximise laboratory time dedicated to assay development.

Europe’s role in advancing the cell & gene therapy industry cannot be overstated. While pharmaceutical companies work to strike the right balance with European authorities on pricing, advancements in cost-saving innovations such as allogeneic therapies or significantly reduced manufacturing timelines continue to progress through to the clinic. It is therefore in every developer’s best interest to carefully plan ahead – from starting materials to safety endpoints – to keep up.

Back to topbutton