CAR-T cell therapeutics have emerged as one of the most revolutionary new treatments for aggressive cancers, with 6 commercial products already approved by the FDA to treat lymphomas and myelomas, and dozens more in development and clinical trial, including treatments for solid tumors. It’s a rapidly growing industry with a sizeable market of eligible patients but, despite commitments by developers to increase treatment capacity, the proliferation of new CAR-T products in fact promises to increase demand at a far greater rate than can realistically be met. Even today, eligible patients routinely fail to receive their treatment, despite being successfully screened.
For more information on CAR-T cell therapies, why not check out our recent blog on the topic?
Why some patients never receive their CAR-T therapy
CAR-T therapies are very high-cost and, due to their complex nature (involving the collection and off-site processing of cells), require significant logistical planning. As such, patients are screened based on a strict range of factors that mean those who fall in the eligible cohort represent some of the very sickest individuals. They are those who have already exhausted other (traditional) cancer treatment options – often 3 or 4 lines of previous therapies – but who are also still sufficiently healthy to receive the additional CAR-T treatment. Nevertheless, due to their precarious nature, it is not uncommon for a screened patient to become weaker or for their cancer to progress further while waiting for their therapy to be manufactured, thus causing them to lose their eligibility status before receiving the treatment.
Further to this, a recent article by Stat News reported that, of all cancer patients who are successfully screened for CAR-T therapies, 1 in 5 will actually pass away while waiting for their manufacturing slot. Not only does this represent an unacceptably high number of people who are failing to receive potentially life-saving treatments, it also means that a significant burden is being placed on doctors and healthcare providers: of all their eligible patients, which will be the lucky ones to receive these cutting-edge therapies?
CAR-T developers are scaling-up capacity to better meet the demand for their products, however they are also simultaneously expanding the volume and range of therapies they offer – and doing so at an even faster rate. For instance, as new solid tumor therapies are launched in the near future, it is expected that the number of patients waiting for a manufacturing slot will also grow exponentially. This means that demand will likely continue to outstrip capacity and, unless optimizations are made elsewhere in the supply chain, a significant proportion of patients will continue to be left behind.
Enhancing the reach of CAR-T therapies
In June 2022, Binocs organized a round table panel with some key players in the CAR-T field, featuring representatives from a treatment center, 2 major developers, and a specialist CDMO; you can read a summary of this insightful discussion in our recent white paper. Based on this and the conversations that followed, we have compiled a list of important areas in which the relevant stakeholders can make changes that could help to improve the reach and success rate of CAR-T therapies.
Increase developer access to trial partners
The small scale of the therapies and the relative immaturity of the cell and gene industry in general make CAR-T a highly attractive field for startup developers hoping to assert themselves within a growing market. A large number of smaller companies competing to develop new therapies can represent definite benefits for an industry – it widens the range of approaches and increases the likelihood of innovative breakthroughs, while ultimately representing a significant opportunity to expand the market availability of novel treatments for patients. Nevertheless, having been established by traditional biopharmas with different business practices, the CAR-T space isn’t always organized to accommodate micro developers, who can find themselves severely limited by their size.
For instance, smaller companies can face potentially disabling restrictions once a promising therapeutic approach has been developed in the lab and they begin looking for a suitable treatment center at which to sponsor human trials. Although such sites will necessarily have been accredited by a centralized group such as FACT (the Foundation for the Accreditation of Cellular Therapy), the details of individual therapeutic protocols mean that a sponsor will also seek to conduct an audit to ensure that their specific requirements are met.
Despite the fact that an audit will produce largely the same result irrespective of who conducts it, the variability between different protocols make it standard procedure for each sponsor to conduct an independent, private audit at each treatment center. Every audit represents a lengthy, complex and costly process that requires significant investment in time from both site and sponsor staff and can result in cell labs handling a dozen or more apheresis manuals for different therapies. Not only can this be far beyond the economic and practical reach of smaller companies but such repeat auditing and duplicated practices represent an extreme burden on the healthcare provider, a problem that will only grow with the number of developers moving to trial phase.
By collaborating to develop treatment protocol standards, however, the industry could work collectively towards identifying a unified regulatory approach that removes the need for such duplication of work and provides a shared auditing process. In this way, smaller developers could gain wider access to trial partners and larger developers could accelerate their products to trial; meanwhile, the healthcare institutions themselves could liberate significant resources for patient care and increased treatment capacity, resources that would otherwise be tied-up in endless audits.
Improve source material viability
The final CAR-T therapeutic product that is infused to patients is a known entity with a clearly-defined expression of biomolecules and generally predictable tolerances; this stability, combined with the nature and size of development sites, means that product can be cryopreserved immediately following expansion and harvesting. This significantly extends its shelf life, allowing close control of shipping conditions to ensure that the product reliably reaches the treatment center in a viable state.
By contrast, source material is an heterogeneous substance composed of inherently fragile, living tissue that is highly sensitive to environmental conditions, including temperature, humidity, CO2, vibration and shock. Typically refrigerated, T cells often have an ex-vivo lifespan of only 24-48 hours following collection, after which they are no longer usable; even within that time window, the consistency of the material can be negatively affected. If there are logistical issues that lead to disruptions, the material can be compromised or have a suboptimal yield, resulting in further delays and potentially requiring the process to be re-started with a fresh round of apheresis.
At present, most apheresis centers simply do not have the relevant equipment or expertise to handle the hazardous substances that would be required for cryopreservation immediately following collection (especially for autologous treatments). Nevertheless, guidance from organizations such as the FDA is evolving as new equipment, cryoprotective agents and transportation standards become more accessible. The emergence of such standardization promises to make this process more widespread in the near future, meaning that the viability of source material will improve and there will be less risk of delays in getting the product to patients. Increased external investment in hardware and talent at apheresis centers would greatly benefit the entire cold chain for all developers servicing a site and is therefore highly recommended.
Promote standardization in manufacturing processes
With the growing number of biopharma companies investing in CAR-T cell therapies, there is ever greater pressure to expand production. The journey from concept to a scalable commercial product is beset with significant economic and logistical challenges and, even for companies with an established manufacturing base, capacity may need to be significantly supplemented to meet delivery expectations at trial phase and beyond; for smaller companies, scaling-up from lab tests to human trialing may simply be impossible without outsourcing end-to-end services to a third-party possessing the relevant technical and regulatory expertise.
This has led to an explosion of business for those CDMOs (contract and development manufacturing organizations) who are specialized in cell therapy research and manufacturing. While different companies race to partner with them, the success of the CDMO business model comes with an associated capacity cost as new sites cannot be inaugurated fast enough to meet the demand. Individual sites may have contracts with a range of clients for ten or twenty different simultaneous therapeutic products at various stages of development. Much as with apheresis and treatment protocols, every product typically comes with a distinct set of manufacturing and quality instructions, each with up to a dozen different analytical methods. In every instance, protocols must be learned, procedures trained, and proprietary guidelines strictly adhered-to.
While the individual CAR-T cell therapies are unique, there is fundamentally a limited number of ways for these products to be manufactured using the standard equipment that is available at any given site. As such, CDMOs can find themselves dedicating precious time and resources to replicating equivalent processes and methods in subtly different ways only to produce the same result for significant portions of the manufacturing and testing process. This lack of industry standardization risks causing even greater disruption as increased levels of automation are introduced to the manufacturing process. Although it may not be quite a case of “reinventing the wheel” for each therapy, this problem is nevertheless close to redefining how the wheels are attached to each new model of car assembled on the production line.
As CDMOs increasingly find themselves part of a wider network of facilities distributed across geographies, each potentially overlapping in the production of certain therapies, the problem of different procedures rapidly compounds with each new site. It is therefore to the overall benefit of not just individual sites but the industry as whole – including each competing development organization – to align on a set of basic manufacturing standards that can be used to accelerate the production process and, ultimately, get more treatments to more patients more quickly.
Enhance visibility of manufacturing capacity
In light of the system of distributed manufacturing networks, a single treatment center potentially has access to CAR-T therapy production facilities from at a variety of sites internationally; however, even across such a network, the global manufacturing capacity is severely limited and there are always more patients than can be treated at any given time. As such, there is constant pressure to maximize manufacturing output to meet as much of the need as possible.
Naturally, manufacturing output is directly correlated with the availability and quality of raw materials which, in traditional biopharma production, relies on largely stable sources with lead times on the scale of weeks or months. Assuming a constant supply and reliable capacity, manufacturing optimization is as simple as planning production slots in sequence, one after the other, and ensuring that the relevant resources are available to meet the demand.
In autologous therapy production, however, the source is entirely patient-centric, representing an inherently variable supply chain with timelines measured in hours. As a result, capacity management in CAR-T manufacturing is a continuous trade-off between what a given site has the physical ability to produce and the availability of T-cells, which are subject to a range of highly unpredictable risk factors. A manufacturing slot cannot be planned until apheresis and shipment of collected source material has been confirmed and, even then, there is no guarantee that the tissue will be delivered at the expected time or will be in a usable state upon receipt.
As a result, a delay in starting one manufacturing run can have significant consequences for the next slot in the sequence – should a production site cancel a slot reserved for starting material that is running late or continue with a delayed schedule and risk the viability of tissue due to be delivered for the next slot? Similarly, how should necessary engineering runs be accommodated around unpredictable production schedules?
To avoid losing slots, manufacturing sites need to have access to high quality, live information that will allow them to react in real time. For instance, at a site level, if it is clear that there is a high probability of delay associated with a particular patient’s cells, the planner can ensure that the subsequent slot is kept free to accommodate likely overrun. On the other hand, at a network level, if one site has more capacity, it can be prioritized for slot allocation over sites with busier schedules, ensuring there is a balanced distribution of work and further increasing the likelihood of successful, timely delivery of final product to the treatment center.
New technologies are emerging to assist in this process by providing direct oversight and support to key stakeholders. One example is Binocs, which not only provides resource planning and scheduling services to CDMOs and therapy developers to optimize production runs but also provides a slot-picking calendar to healthcare providers, allowing them to guarantee an appropriate manufacturing slot to match the availability of their patients for apheresis. The adoption of such systems is encouraged to streamline end-to-end processes that will enhance user experience for all stakeholders in the value chain.
Expand the availability of treatment sites
During these still early days of CAR-T therapeutics, the standard model of treatment requires highly specialized, inpatient centers, in which patients can be closely monitored in the days following infusion due to the risk of adverse events (such as fever, sepsis, cytokine release syndrome, and neurotoxicity). However, due to an increased familiarity with protocols and greater confidence in identifying early signs of a reaction, recent studies suggest that 1 in 2 CAR-T therapy patients may, in fact, not require any hospitalization following treatment at all.
Keeping patients in hospital unnecessarily not only means that vulnerable individuals are isolated from the home comforts and loved ones that can promote recovery (often for extended periods), it also severely limits the number of patients who can be treated simultaneously due to restricted bed numbers at site. As the curative potential of these products is inevitably expanded to new disease groups in the coming years, a stepwise increase in treatment capacity must be achieved.
Thankfully, processes are becoming more established and standardized and new methods are emerging to streamline treatment procedures, including the development of specialized and refined post-infusion observation protocols. Today, there is an increased interest in delivering CAR-T therapies in the outpatient setting and only transferring to inpatient treatment if and when adverse events do occur. This promises to greatly broaden access to treatment centers, increase treatment capacity and generally improve the allocation of healthcare resources.
In the short term, simple logistics mean that the biopharma industry is unlikely to successfully meet the rapidly growing patient demand for CAR-T cell therapies. Despite this, there are a range of different solutions – some of which are described above – that could optimize the current rate of therapy and help to expand capacity moving forward. A recurrent theme in these solutions is the need for the industry as a whole to come together and promote certain standards and practices for general implementation across apheresis, manufacturing and treatment sites.
As new industries emerge and explode in demand, there is always fierce competition to safeguard aspects of the associated novel technologies and procedures, sometimes at any cost. As an example, by the mid-19th century, the burgeoning US rail network was serviced by over 300 different, private railroad companies, each defining the gauge of the lines it operated. Often, those gauges were set specifically to restrict competitors and stop them from traveling on their lines – even though this ultimately meant that they could also not operate on their neighbors’ lines. As transcontinental travel became increasingly desirable, the pressure from cargo companies and passengers mounted to the point where an agreement on standardized gauge sizes was reached between the different operators – although it took 50 years!
There is a lot the CAR-T industry could learn from this example to avoid a similar level of competitive disconnect, hopefully working to somewhat more rapid timelines. At the end of the day, the most important stakeholder in the industry is the patient and initiatives to prioritize their access to critical treatments should definitely be “railroaded”.
Interested in learning more about perspectives on the cell and gene industry from key stakeholders involved in CAR-T cell therapy development, manufacturing and treatment? Why not download our white paper on industrializing the next generation of cell and gene therapies!