Daniel Gibson, Head of Innovation and Commercialisation talks about the advancements in cellular therapy research, and how we are overcoming critical issues in the supply of Advanced Cell Therapies.
When Alexander Fleming returned to work from his family holiday, on that fateful September day in 1928, and saw his staphylococci colonies being wiped out by an accidentally introduced mould, he had no idea that he was about to transform the entire field of medicine. That serendipitous discovery of penicillin has saved the lives of thousands of people since then, but it has taken an army of coordinated and resolute researchers in the antibiotic field to extend that initial discovery into the panoply of medicines we have today, and the millions of people who are still alive as a result.
Overcoming critical issues in the supply of advanced cell therapies
It’s hard to imagine any breakthrough today could have an impact on the same scale, but cellular therapies and personalised advanced medicine could be poised to do just that. Years of painstaking research and huge amount of investment has brought us to a potential tipping point, and we now have the first two advanced cellular therapy products approved for humans.
Complex problems often require complex solutions, and with childhood acute lymphoblastic leukaemia and advanced lymphomas as the target, it is no surprise that the first two approved advanced cellular therapy products utilise a complicated adoptive cell transfer approach. But the less of that complexity we can introduce, the faster our research and trial processes can become, and one of the easiest ways to reduce the variables and complexity, is by getting smarter in the way we select, use and transport the starting materials for the programmes.
We have been working with and supporting biotherapy researchers for many years now, and in our experience, there are several critical factors that can have a notable impact when developing advanced therapy medicinal products (ATMPs) from idea, to trial to routine medicine.
3 key factors to consider
1) Starting material quality
How do you qualify your starting material? It is essential to understand the factors of incoming product variability; every donor is different! Where selection cannot be applied it’s important to know whether the downstream process controls can compensate for the levels of variability in order to produce a standardised and defined end product. For example the starting number of your target cell type will almost certainly be a critical factor. Too few cells and the process may not show an economically sensible return whilst too high could alter the growth or transformation kinetics.
It may be possible to compensate for this with process controls and appropriate dosing but where the controls are not possible pre-screening, it's essential to ensure the end product remains defined. If the risk of process failure can be avoided through critical evaluation of the starting material this will save money in the longer term as typically the starting material is a relatively small proportion of the overall process costs.
The source material is an important consideration. In cord blood, for example, we observe that the number of nucleated cells and stems cells is dependent on the collection modality (natural vaginal delivery vs caesarean section). Mediated by stress, prior to the point of collection, the starting materials could potentially be different. Likewise in the adult stem cell setting, it is well know that patients fair better when a donation comes from a young male. The donor variability shouldn’t be overlooked and therefore working collaboratively with the source provider to understand and control the incoming product should be encouraged.
2) Regulation and consent
Currently, most products are autologous however there is a growing appetite for allogeneic cell sources to provide ‘off the shelf’ medicinal products. There are a couple of complications here; firstly access to such donor material. This is dependent on the source material required. Cord Blood for example, is readily available whereas obtaining adult donors can be more complicated. In the early stages of process design and qualification through the Investigational Medicinal Product Dossier (IMPD) there is no guarantee that any given donated product will yield any patient benefit. While the long term benefits are unquestionable, consulting and consenting donors onto an invasive protocol raises some important ethical questions which need to be overcome.
Secondly, the ability to provide excellence-in-service and excellence-in-product require multi-state collaboration so the application is borderless. The regulation around importing and exporting human derived cells for human application are understandably robust. The sector needs to work collaboratively to overcome any issues to ensure ease of access and full regulatory compliance.
Lastly, the ability to deliver the desired and tested effect is dependent on scaling the production within the tested parameters. If the process is dependent on quality of starting material, which is adversely affected by, for example, age of cells at point of processing, length in storage or storage condition then these factors need to be well controlled and adhered to. Similarly to qualifying the source material, these logistical factors need to be qualified, standardised and controlled.
Likewise for the distribution of manufactured products, the big question a number of years ago was whether the products can be manufactured close to the patient through disseminated processing thus overcoming logistical and stability concerns, or to centralise the processing expertise into a central processing centre and distribute the material. Whilst still important to consider at an early stage, most approaches now look at the latter solution which again requires collaborative approach to ensure the integrity and regulation is upheld.
Fleming famously said, “I certainly didn't plan to revolutionise all medicine by discovering the world's first bacteria killer or Antibiotic. But I suppose that was exactly what I did!” His discovery yielded a whole new arsenal of medicinal products to treat some of the world’s greatest killers, leading to his knighthood in 1944, his Nobel Prize in 1945, and his recognition by Time magazine as one of the most important people of the 20th century.
ATMP is offering the potential for a whole a new age of medicine; a futuristic age where tissue and cellular engineering provides unprecedented treatment options. Whilst trial data is exciting and the regulators are now approving ATMP’s, more work is needed in the support services around the science before we see advanced personalised medicine opened to the masses. The quality of the starting material, the regulations and the logistics are by no means an exhaustive list but at the same time no small feat, which will require collaborative, multi-agency approach to overcome.