Marcos Langtry (Lonza, Basel, Switzerland) discusses the advantages of allogeneic therapies, the challenges to quality and production, and the future of the cell therapy field.
Can you introduce yourself and tell us about your role?
I have worked within the pharmaceutical industry for several years. During this time, I have had the opportunity to hold a variety of positions, from technical and operations to strategy and commercial. In my current role at Lonza (Basel, Switzerland), I lead the commercial strategy for the allogeneic cell therapy business, including managing current and future offerings, pipeline and portfolio optimization, innovation strategy and investments. My portfolio covers all allogeneic areas including stem cells, induced pluripotent stem cells (iPSCs), immortalized and engineered lines, CAR natural killer or T-cells and exosomes.
The opportunities for cell and gene therapies to bring value to patients globally are many, and I am very keen to contribute in my role at Lonza to the advancement of the field by offering therapy developers a trusted partnership for their development and manufacturing needs.
How will allogeneic therapies move beyond close-relation donors?
The majority of allogeneic cell therapies under development are not donor matched. This is true for mesenchymal stem products, which are immune privileged cells, but also for many allogeneic CAR-T and iPSCs products. For some therapies, such as CAR-T, patients often undergo an immune suppression regimen for lymphocyte depletion before transfusion. Allogeneic CAR-T TCR knock-out strategies are being developed to avoid unintended targeting of the therapeutic cells by the immune system.
The benefits of HLA matching have been studied for the different cell groups. These include some CAR-T therapies developed with matched HLA, intended to avoid graft-vs-host disease. For iPSCs, there have been some studies indicating that banking cells from a combination of HLA-typed volunteers can minimize requirements for immunosuppression for a given population. This path could be less technically challenging for countries with lower genetic variability, like Japan, whereas for large and very diverse countries, like the USA, this would be more challenging.
How could allogeneic donors be better utilized in CAR-T therapy?
Super donors represent a step towards a superior starting material. By identifying the critical quality attributes required from the donor, for a given process and indication, therapy developers can select donors who are naturally more suited to their process or for the target indication.
Super donors represent a step towards
a superior starting material.
Generally for allogeneic cell therapy, bio-banking of healthy human donors could reduce time to manufacture. This would decrease the reliance on using cord blood banks, while enhancing the availability and potentially the quality of the starting material by banking in more defined conditions.
What specific challenges may allogeneic therapies face in their manufacturing over their autologous counterparts, and how can Lonza help address these issues?
There are several specific manufacturing challenges faced by allogeneic therapies. Starting from tissue acquisition, allogeneic cell therapies depend on individuals that voluntarily donate tissue for scientific, clinical and/or commercial objectives.
The legal and regulatory hurdles to obtain these tissues are complex, and regulations vary considerably from country to country. At Lonza, we have the advantage of being able to leverage the knowledge of a dedicated tissue acquisition team, with over 20 years of experience, who stay current on donor screening and testing requirements as they change. They can make the tissue acquisition journey from clinical development to commercialization straightforward.
Lonza has a defined model to ensure successful manufacturability and a clear path to clinical/commercial…
The master cell bank concept, required for allogeneic therapies, brings its own distinct complexities. Besides the need for a very comprehensive characterization of the cells, there are very stringent requirements for safety, in particular viral testing, where the absence of adventitious and endogenous virus needs to be verified.
With a market that is rapidly growing, demand can quickly outpace supply, especially for regulatory agency cleared raw materials, leading to long procurement lead-times. This is even more acute for biologic materials with a limited global supply, such as fetal bovine serum (FBS), driving an urgent need to switch to alternative media.
Lonza has a defined model to ensure successful manufacturability and a clear path to clinical/commercial, based on a 3-step approach for introducing new projects. It starts by ‘diagnosing to de-risk’ to establish the baseline process, identify the major manufacturability gaps and come up with the scope of development activities; we then ‘develop and industrialize’ the process, where phase-appropriate process optimization and development is performed, based on manufacturing design specifications and critical quality attributes. Lastly, we ‘deliver to GMP’ with a clear focus on transferring the manufacturing process into our cell therapy suites to start GMP manufacturing.
This approach balances the need for speed at the early stages with the robustness and reproducibility demands of future commercial manufacturing, thereby avoiding costly manufacturing failures and providing reliable clinical and commercial supply.
What lessons from the manufacturing of autologous product can be applied to allogeneic products?
Traditional processes tend to be labor intensive. They often rely heavily on manual operations requiring long processing hours burdening the workforce. Many of these processes are open, and hence at risk from contamination issues, even with stringent aseptic training and qualification. As we scale up, reproducibility could be affected by the long process duration and the large number of personnel required to complete all activities.
Raw material supply can become a bottleneck. A key learning from autologous cell therapy is to focus on security of supply, with a sustainable source that allow us to scale-up without compromising the process. Allogeneic therapies rely on greater batch sizes, with material costs per batch sometimes becoming astronomical. There is a need for a large quantity of high-quality materials, sometimes single sourced, from reliable vendors. Cell factories, consumables and media are needed in significant numbers as processes scale up to meet late-stage and commercial-volume requirements.
Raw material supply can become a bottleneck. A key learning from autologous cell therapy is to focus on security of supply…
Allogeneic cell therapy needs to build on the transition towards automated, robust and reproducible closed processes that can be easily scaled up to allow us to achieve lower cost of goods (COGs). This is critical to provide the necessary price flexibility to enable allogeneic cell therapy to reach all patients who can benefit from it, many of whom are seriously ill.
What are the specific challenges that need to be addressed when dealing with the allogeneic sources for immunotherapy?
I believe the main challenge we need to address, from a manufacturing perspective for allogeneic cell therapy, is the scaling of the process. Some rare diseases need high cell dosage, while larger indications reach more patients and require a large batch size to be able to supply the market in a cost-effective way.
For allogeneic CAR-T cells, in particular, we need to work in parallel on overcoming upstream scale-up challenges, by defining optimal solutions to generate the volume of cells needed for multiple doses (at the desired quality),as well as on the downstream technologies, to be able to select and purify the target cells at the given scale. These tools do not exist today. Significant development will be needed, in sync with the fast-evolving pace of the manufacturing needs.
How could quality control procedures adapt to the mass manufacture of allogeneic products?
Significant attention is needed towards process analytical technologies. Process control and quality control are key to developing the robust scaled-up operations we need to deliver.
The implementation of appropriate analytical methods is important as we drive to closely monitor and control process variables that could impact quality.
For quality control testing, allogeneic has its own particular advantages and disadvantages. From the safety perspective allogeneic requires a safety set of sterility, mycoplasma and viral testing, which is very time consuming — particularly the latter. Nevertheless, allogeneic also brings the opportunity to be able to manufacture the product in advance with an off-the-shelf supply, which can undergo full testing. This is an advantage versus autologous, where conditional release followed by full release is often needed.
Process control and quality control are key to developing the robust scaled-up operations we need to deliver.
One other aspect to consider is particulate inspection. The manual visual inspection of the finished product may become a bottleneck and at that stage, semi-automated or fully automated inspection processes would likely be needed. However, currently there are not many cost-efficient automated technologies validated for cell therapy.
Finally, mass production of allogeneic products will likely trigger the need for comparability studies. These studies will be needed to increase capacity, by either scaling-up an existing process at a given site, transferring a process from a donor to a receiving facility, or both. Although the full requirements of comparability studies are not always identical, all studies are based on an in-depth understanding of the cell functionality and the product’s critical quality attributes. Solid functionality assays and characterization will therefore be critical for successful comparability and consequently for having enough capacity to supply the market.
Which areas of medical research do you think will benefit most from access to allogeneic therapies?
Due to their cost structure, allogeneic cell therapies are intended to be significantly more economical and hence likely to raise strong interest from all parties.
Today, allogeneic therapies are popular with cell restorative therapies, e.g. diabetes, Parkinson’s or stroke, where the cell is secreting trophic factors into the body, and also with target sites that are immune privileged, such as the eyes. Allogeneic natural killer and T-cells are also increasing rapidly based on their off-the-shelf advantages and cost-effectiveness.
What do you think the future of allogeneic therapies will look like?
The current level of investment is unprecedented, and we are now realizing the life-saving and life-changing benefits these therapies provide for the approved indications.
I personally believe there will be space for both allogeneic and autologous therapies in the market. I see allogeneic cell therapies better addressing larger indications, for which they are particularly suited from an availability and a pricing perspective. At the same time, autologous opportunities are very well suited for rare diseases, where their allogeneic counterparts are not likely to be cost-effective to produce, or for any size indication when their efficacy and safety profile is better.
How should people contact you if they wish to?
My email is [email protected]. I am happy to be contacted and will be looking forward to work together.
If you are interested in further discussing your process development needs, you can find more information at Lonza Pharma and Biotech.
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