If you ever heard a talk or read a paper on translation of cell therapy, you may remember a mention of scaling up of cell manufacturing as a criteria of success. Scaling up here is two-fold: (1) production of large cell quantities via expansion ex vivo and (2) large expansion of manufacturing capabilities via construction of facilities and multiplication of materials/ devices. I’d argue, that scale up is frequently not the case for cell therapy success. It is certainly true for some cell therapy models, but not for the others. I’d like to emphasize the importance of potency of cellular product over the scale of cell expansion and production. Of course, I’d like to hear your opinions and welcome any discussion.
When do we really need to scale up?
First of all, I’d like to mention for what kind of cell-based therapies scale really matters. The first example is tissue engineering and whole organ bioengineering. To build a tissue and organ prototypes we need huge number of functional cells – from many many billions to trillion. We definitely cannot avoid scaling up of cell production in order to succeed. This is a good example of cell culture scale up – related to generation of large number of cells for one product. The next example is centralized manufacturing of allogeneic cell-based therapeutics for diseases with high prevalence (ex: heart failure or eye diseases). In this case cell manufacturing plant has to produce thousands to millions of doses of the cellular product. One dose may not contain many cells – it could be anything from few to one hundred millions, but number of doses per batch is big. This is an example of the second type of scale up – related to manufacturing capabilities. In centralized model of cell manufacturing everything should be big – size of the plant, number of workers, number of devices, number of production rooms and so on.
Unmanipulated hematopoietic cells
Now, when we don’t need to scale up. Let’s start from minimally manipulated cells and look at stem cell transplant in hemmatology-oncology. Even though, there is a goal for minimal dose of CD34+ cell to predict good engraftment (usually >2.0 – 2.5 millions per kg), the more is not always the better. Hematologists don’t like to transplant more than 15-20 millions per kg of CD34+ cells, because some related complications may occur. So, in the range of 2.5 – 15 millions per kg of CD34+ cells, the outcome frequently the same among different patients and different centers. Interestingly, the minimal dose of CD34+ cells for successful engraftment in cord blood, could be 10 times less than for mobilized blood and bone marrow. It means that CD34+ cell potency and population composition matters more than quantity. In this example, hematologiists know precisely how many CD34+ cells they need for success and one graft can provide this desired number (no expansion necessary). The scale up of central manufacturing in this case is also not necessary, since technology is very robust and reproducible, well defined and disseminated all over the world as non-commercial therapy.
Autologous scale out model
The next example is autologous advanced cell therapies, where we need cell expansion, but instead of scaling up, we are scaling out. In autologous scale out model 1 product = 1 small batch = patient. This is fundamentally different from scaling up. No huge bioreactors or oversized materials required here, but rather small-sized single-use disposables. It is not clear at this point, how autologous scale out model will be translated and integrated into wide clinical use after approvals. There is a number of proponents of decentralized manufacturing, where every mid-size hospital will be capable to produce such cell therapeutic analogously to stem cell transplant in hematology. As of now, we have one example of unsuccessful centralized manufacturing for autologous scale out cell therapies – Dendreon.
Engraftment/ function plateau rule
Engraftment rule says that at certain number of exogenous transplanted cell dose, there will be neither increase in engraftment nor increase in functional outcome with continuing cell dose increase. This is true for hematopoietic CD34+ cells in hematology (as mentioned above), as well as for cells expanded ex vivo. We can see the proof for this rule in numerous experimental studies (for example, cardiospheres in cardiac disease model and neural cells in spinal cord injury model) as well as in some clinical trials. Because the optimal cell dose is usually unknown, many cell therapy trials frequently designed as dose defining/ dose escalation. At some point, most of these studies (1) get to the point of function plateau rule, where outcome will not change with increase cell dose and (2) conclude that 5-100 millions cells is enough.
Large scale cell expansion is not always good
There is an ongoing discussion, initiated by Jacques Galipeau, that large scale expansion of mesenchymal stromal cells by commercial manufacturers may compromised their therapeutic potency. It is definitely good for allo-/ central manufacturing business models, but may not be good for cell function in each produced dose. There is a number of other adverse effects of prolonged cell culture and massive cell expansion.
Lessons from CAR T-cells
CAR T-cell field is kind of unique, because expanded and genetically modified T-cells continue to divide in human body after transplantation. One of the most challenging questions here is how to dose dividing drug? Nobody knows the answer! CAR T-cell therapy provided one of the most dramatic examples of importance cell potency over quantity – as low as 0.15 millions/kg of T-cells sent leukemia to remission. These CAR T-cells expanded inside of the patient >1000 times! Yet another example was given in recent presentation by Carl June (watch from min 18:15) – 98% of CART+ cells in patient marrow were derived from one clone (progeny of single cell). So, essentially one potent cell caused leukemia remission. So, we need very very few CART cells, but very potent and persistent. The trick is how make them very potent in culture.
To conclude – I was trying to give few examples, where scaling up in cell therapies is not a critical factor for success. Do not get obsessed with the scale. Get obsessed with cell potency instead.