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Volume 33, Issue 2
The commercialization of cell therapies is still at its infancy, but industry is facing an exciting period of development as the sector is expected to grow exponentially.
As the incidence of chronic diseases, such as cancer, is rising, so too is the interest from industry in the area of cell and gene therapies. According to market research, the global cell and gene therapy market is projected to grow at a compound annual growth rate of 24% between 2018 and 2024 (1), driven by the increasing prevalence of chronic diseases, launch of new products, regulatory support, and improved manufacturing expertise.
“The entire cell therapy field is in its infancy,” confirms Jason Fontenot, senior vice-president, Cell Therapy, Sangamo Therapeutics. “Every aspect of cell therapy is in an exponential growth phase.”
Martin Lachs, head of the Oncology and Cell Therapeutics Project Management Group at ICON, an Ireland-based clinical research organization, notes that the promise of personalized medicines has been anticipated for a long time, with tangible and real effects of years of research into the human genome finally coming to fruition. “While oncology was the initial focus in cell and gene therapies, we’re now seeing a significant pipeline for rare/orphan diseases and other therapeutic areas,” he says. “At a recent conference on regenerative medicine (2), it was estimated there are over 1000 cell and gene therapy trials globally (650 in oncology)-and over 100 of them have received designations for expedited approval.”
A main driver of growth in cell and gene therapies for Keith Thompson, chief executive officer at the Cell and Gene Therapy Catapult (CGT Catapult), has been the impact of chimeric antigen receptor T cell (CAR-T cell) therapies. “These therapies use the genetic modification of cells to augment the cell-mediated immune response,” he adds. “Of particular note is the well documented successes of CAR-T cell therapies for hematological malignancies, which have transformed the therapeutic landscape and paved the way for a surge in cell and gene therapy trials.”
Industry has invested hugely in autologous CAR-T therapies following the approval of the first CD19 targeted CAR-T therapies, specifies Fontenot. “The major areas of innovation within oncology cell therapy are ‘off-the-shelf’/allogeneic approaches and natural killer (NK) cell approaches,” he continues.
“Arguably,” says Lachs, “the commercially approved cell therapies Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) have not realized the full potential hoped for in the marketplace as first-generation marketed CAR-T products. Even with such CD-19 targeted products, the trajectory is to bring these approaches closer to front-line treatment as opposed to limiting to relapsed refractory acute lymphocytic leukemia or lymphoma and to improve safety and durability of response.”
For Lachs, the next product that will be seen on the market will be autologous B cell maturation antigen (BCMA) target CAR-T cells in multiple myeloma. “Approaches to circumvent antigen escape, T-cell exhaustion, and so on, are focus areas with the advent of bi-specific constructs, for example,” he adds. “Additionally, combinatorial approaches with other immune regulating antibodies that impact the tumor/immune environment such as PD-1 are potentially promising.”
New indications have also been making waves in the industry. “Research into overcoming barriers to the use of genetically modified immune cell therapies for solid tumors is ongoing and showing promising results, especially with T-cell-receptor-engineered T cells showing great potential,” notes Thompson.
The very nature of cell therapies, the fact that they are “living” drugs, makes their development much more complex than for other biological therapies, explains Fontenot. “The major challenge in cell therapy is developing a very defined drug product in which there are well-defined characteristics that are correlated with outcomes,” he says. “The donor-to-donor variation and the manufacturing process can introduce a huge amount of variability into the product and it is often unclear which attributes are driving efficacy and safety.”
Manufacturing and logistics are key differentiating factors between cell therapies and other biologics in Lachs’ opinion. “Producing viable, sterile autologous cell products that are also not contaminated with tumor cells and moving starting materials-the patient’s own cells-through the vein-to-vein process is certainly fraught and requires extraordinarily tight control,” he stresses. “The growth of specialist software platforms and logistics companies is a testimony to those challenges.”
Additionally, the growth of contract development and manufacturing organizations (CDMOs) to take on the burden of manufacturing cell therapies is a signal of the complexities of development of these therapies, Lachs continues. “For allogeneic products that use donor cells to treat many patients, the challenges of cell therapy development are somewhat ameliorated such as viability, but they are by no means dispensed with as the potential development of graft versus host disease comes into play,” he notes. “Maintaining chain of custody, chain of condition, and chain of identity are critical elements in a very complex supply chain that involves numerous stakeholders and handoffs.”
The uniqueness of cell therapies-the fact that they are living medicines and, when autologous, personalized to the patient-leads to significant therapeutic advantages, such as increased effectiveness and reduced chance of host rejection. However, Thompson emphasizes that the therapies also give rise to challenges throughout the manufacturing and product cycle.
“Each patient sample requires its own process,” he says. “A specialized manufacturing process is vital to ensure that these living medicines are developed safely, efficiently, and do not compromise the sample. Autologous cell therapies don’t require a scale-up of production (larger volume), but rather a scale-out (i.e., a larger number of parallel processes) to be able to manufacture at scale. Because of this, many of the manufacturing processes, facilities, and regulations required to produce cell therapies have only been established in the last few years as therapies started to reach clinics.”
Handling of cell therapies is also unique, with timing critical and tracking equally so, due to safety and the irreplaceable nature of the starting materials, Thompson asserts. “Particularly for autologous therapies, quality is an important consideration,” he says. “Further challenges in development may arise because the initial sample can be compromised as a result of the patient’s disease.”
Furthermore, regulations are inevitably more complex. “Cell therapies often involve multiple elements, such as gene modification, activation of cells using viruses or other vectors, which need to be tightly regulated,” Thompson adds.
An overwhelming challenge for developers of cell therapies is cost. These complex therapies are expensive to progress through the various development cycles and, given the manufacturing and logistics challenges that they give rise to, funding is more than likely required via venture capital or collaborations. “The stop-start nature of trials owing to rapidly emerging (safety) data, which results in numerous protocol amendments, manufacturing glitches etc., places profound pressure on the development cycle,” confirms Lachs.
The lack of long-term data could be adding to the development challenges of cell therapies. “Despite the fact that the results being seen from currently available therapies are remarkable, evidence for long-term efficacy is still accumulating,” says Thompson. “Added to the production costs required for cell therapies, additional questions are raised over the suitability of current reimbursement schemes.”
Access to autologous cell therapies is also challenging. “Off-the-shelf approaches are the future,” states Fontenot. “Developing drug product attributes (i.e., cell phenotype of functional measurements) that are well correlated with outcomes is important but very difficult. Also, animal models are even more limiting than in the small molecule and biologics spaces. One can only use immunodeficient animal models to evaluate human cell therapies, which is very limiting.”
As companies start to move towards solid tumor targets, the ability to obtain tissue for the production or expansion of cell therapies adds another burden, continues Lachs. “The treatment of patients with advanced solid tumors has become more dependent on tissue biomarkers to help guide management decisions,” he says. “Targeted therapies are associated with superior clinical outcomes, but to obtain updated biomarkers and targets, large biopsy specimens are often needed. This not always feasible either because the lesion(s) are not safely accessible to a surgeon or an interventional radiologist, or because the patient declines further invasive procedures.”
From a commercialization perspective, the cleanroom space to enable manufacture of cell therapies at scale could be problematic, notes Thompson. “Additionally, as companies progress towards commercialization of cell therapies, they require more personnel with the specialist skills required, but the appropriate schemes need to be put in place to provide training in these skills and widen the talent pool,” he says.
There are several potential solutions available that could help overcome some of the challenges associated with cell and gene therapy development. “Renewable cell-source-derived (e.g., induced pluripotent stem cell [iPSC]-derived) cell therapies have the potential to greatly increase patient access and introduce more uniformity into the process,” states Fontenot. “Using ‘omics’ approaches to characterize the drug product pre-infusion and for follow up of patients post treatment is also a major area of focus, as it can help identify key attributes to correlate phenotypes and outcomes.”
Specifically looking at the United Kingdom, Thompson reveals that a collaborative ecosystem, where companies can work with government agencies, regulatory bodies, the industry, and healthcare system, can prove to be advantageous. Moreover, strong government support of facilities, such as the Cell and Gene Therapy Catapult development and manufacturing centers, and initiatives that have been set up to help companies, such as the Advanced Therapies Apprenticeship Community, can aid development of advanced therapies and growth of the industry, he adds.
In addition to the many approaches available to tackle the scientific challenges, costs associated with cell therapy development may, in part, be addressed via successful allogeneic or ‘off-the-shelf’ products. “Allogeneic or ‘off-the shelf’ products avoid some of the obvious logistical complexities of modifying the patient’s own cells and all that this entails,” Lachs says. “Obtaining cells from healthy individuals improves the likely viability of cells circumventing T-cell exhaustion and contamination with rogue cells. That is not a sure thing.”
However, Lachs warns that allogeneic approaches need to circumnavigate the tissue-matching phenomenon, which means that human leukocyte antigen typing becomes key in many, but not all, cases, potentially limiting the target population. “Generally, it is held that graft versus host disease is not a major feature for allogeneic T-cells in more advanced development,” he says. “The ability to produce hundreds of viable cells for multiple infusion is very compelling from a treatment and cost perspective.”
“There is a long-standing desire to move from autologous to allogeneic CAR-T cell therapies, predominantly because of the improvements ‘off-the-shelf’ therapies promise for the accessibility, logistics, and cost of CAR-T cell therapies,” Thompson confirms. “Other potential benefits of allogeneic CAR-T cell therapies are that samples would be provided by healthy donors, and they could be used more immediately than autologous therapies thus limiting disease progression during the manufacturing process.”
In Lachs’ opinion, there will be three areas that will witness significant developments over the next 10 years. Firstly, he expects that industry will conquer the obstacles created by the local tumor environment, opening the opportunity to successfully tackle a broader range of particularly solid tumors. Secondly, he notes that “manufacturing of cell therapies will become automated and much cheaper, making the generation of both allogeneic and autologous cell products faster, easier, and cheaper.” He adds that, “both allogeneic and autologous approaches will have a role in the future, and one will not supplant the other.” Thirdly, Lachs continues, “cell therapies will find extended utility in a breadth of therapeutic indications, such as neurodegenerative disorders and rarer enzymatic pathologies.”
Agreeing with Lachs, in part, Fontenot specifies that major trends will be the use of cell therapies outside of oncology, in addition to “off-the-shelf” options. “Renewable cell-source-derived products will be a huge focus,” he says. “The other trend will be toward more highly engineered products-more gene editing, more complex engineering. I believe the next major breakthrough will be engineered regulatory T cells. I am convinced that these cell products have the potential to cure autoimmune diseases.”
Further commenting on gene editing, Thompson adds that it will have a crucial role over the next decade as researchers search for new ways to target and treat the underlying causes of diseases, as well as accelerate advanced therapy development. “Pluripotent stem cells have long held the promise of producing major classes of stem cell-derived treatments; however, this field has somewhat lagged the gene therapy and gene-modified cell therapy field,” he notes. “Much of the enabling work has taken place with embryonic stem cells, and we have seen some results in the clinic, for example in ophthalmology and diabetes. Significant investment has gone into iPSC-derived cell therapies, and we are now seeing expanded corporate activity. We expect to see more early stage clinical work which, if successful, is likely to drive another big wave of investment and clinical development.”
Methods used to scale up vector production for clinical trials and commercial supply will also be an area that will see progression, according to Thompson. “Advancements in methods used to scale up vector production will be essential to meet demand as the number of trials and approved therapies continues to grow,” he says. “And as already discussed, there will certainly be developments and new generations of cell therapies of all types and modalities for a wider range of diseases, and new strategies will emerge to improve the manufacture and delivery of autologous and allogeneic therapies. It’s truly an exciting time for developers in the industry as we start the new decade.”
“While we are continually challenged with lack of standardized processes and systems, the industry will continue to learn and evolve with best practices to support scalability and access,” concludes Lachs. “It’s indeed an exciting time in medicine understanding that cell and gene therapies work-and save lives.”
1. Arizton, “Cell and Gene Therapy Market-Global Outlook and Forecast 2019–2024,” arizton.com, Market Report, November 2019.
2. Alliance for Regenerative Medicine, Cell & Gene Meeting on the Mesa (Carlsbad, CA, USA, October 2019).
Vol. 33, No. 2
When referring to this article, please cite it as F. Thomas, “Cell Therapies: The Living
End of Growth Opportunities,” BioPharm International 33 (2) 2020.