January 31, 2023 PAO-01-23-NI-01
Patient-specific chimeric antigen receptor (CAR)-T cell therapies have changed oncologic immunotherapy and greatly improved the lives of many patients affected by hematological cancers. Since the first engineered T cells were developed at the Whitehead Institute at MIT in the early 1990s,1 six CAR-T cell therapies have received U.D. FDA approval for the treatment of acute lymphoblastic leukemia, mantle cell lymphoma, large B cell lymphoma, and relapsed or refractory multiple myeloma.2,3
Autologous CAR-T cell therapies have demonstrated significant efficacy in patients with aggressive, advanced disease.4 Using the patient’s own cells avoids any risk of immune reaction against donor cells. Modified patient cells also persist for months and sometimes years, enabling a positive response to the treatment for the long term.
The inherent nature of patient-derived CAR-T cell therapies create challenges, however. Questions exist about scalability, logistics, and cost, as well as with raw material variability and cell quality.5
The patients considered for most CAR-T cell therapies have cancers that have resisted all other forms of treatment. Their immune cells have been exposed to chemotherapy and radiation and often other modern immunotherapies, and as a result their quality (e.g., numbers, viability, purity, CAR expression) is often reduced and variable from one patient to another.2,5,6 This variability can lead to manufacturing failures. Kymriah® (Novartis) has experienced manufacturing failure rates as high as 9%.7 Similarly, the durability of autologous CAR-T cell therapies can be less than desired.6
Since to date CAR-T treatments have been viewed as a treatment of last resort, limited numbers of patients are considered candidates.2 Many of those patients do not receive the therapy, however, because they do not live near the limited number of treatment centers and cannot travel to one of these locations. Some that do qualify become too ill while waiting to have their genetically modified cells returned to them once they have been shipped off to the central manufacturing site, a process that can take many weeks.8
The logistics of the manufacturing process are also extremely complex and require exquisite timing at the hospital and manufacturing site. There are risks of cross contamination. Patient cells — both the raw material and the treatment — are sensitive and prone to damage.4
Furthermore, production of autologous cell therapies cannot be scaled up but must be scaled out, given that one batch is made for one patient. Clinical trial materials are often produced in biosafety cabinets using open flatware and many manual manipulations, an approach not practical for commercial production. Both issues contribute to high costs and create challenges with respect to reimbursement.2
With regard to cost, the American Society for Transplantation and Cellular Therapy recommends that hospitals bill four to five times the drug price for CAR-T cell therapies, which is typically several hundreds of thousands of dollars.9 Cure rates must be sufficiently high to make autologous CAR-T cell treatments cost-effective.10,11
Closed, automated processing systems are being developed to increase efficiency, reduce risk, and minimize error. They are also enabling decentralized manufacture of CAR-T cell therapies, which should increase accessibility and reduce costs by eliminating the complex logistics and extended times required for product production.12 There is also movement toward the use of CAR-T cell therapies as earlier-line treatments. Banking of patient cells harvested upon first diagnosis is being explored as a means to improve cell quality.
Donor-derived allogeneic CAR-T cell therapies offer many advantages compared with autologous, patient-derived treatments.14 These off-the-shelf therapies are readily available, with no need to modify patient cells, either at a central manufacturing site or at the point of care.
Production would be implemented in a manner similar to that for conventional biologics, with large quantities produced in a single batch and filled into vials for storage and distribution as needed. The ability to produce large numbers of doses per batch for multiple patients would also contribute to lower costs.2 In one study completed in 2018, it was calculated that the cost to produce an allogeneic CAR-T cell therapy at larger scale could be as low as $7,500–10,000 per dose.13 Owing to both the lower cost and available inventory, access would be greatly increased, particularly in countries that lack appropriate infrastructure.4
Therapies could also potentially be developed for more prevalent diseases, and genetic modification of multipotent stem cells could possibly allow development of therapies that could treat multiple diseases.15 Furthermore, careful selection of donor cells would lead to consistent and higher raw material quality and facilitate the development of more robust and predictable manufacturing processes.2,6
As importantly, the safety and efficacy of allogeneic CAR-T cell therapies appear to be similar to comparative autologous treatments with respect to rates of cytokine release syndrome (CRS), with mostly low-grade (grade I-II) graft versus host disease (GvHD) observed.16,17
GVHD remains one of the biggest hurdles that must be overcome if allogeneic CAR-T cell therapies are to become successful.2,5,6 Immune-mediated rejections, such as GvHD, in which the donor cells are attacked as foreign threats, have the potential to be life-threatening. It is also possible for allogeneic cell therapies to be rapidly removed from the body, dramatically reducing their therapeutic effects.2,4 In addition, if antigens are generated, redosing can be difficult as well.
There are additional challenges to the scale-up of allogeneic CAR-T cell therapies. Access to sufficient quantities of high-quality viral vectors for genetic modification of the donor cells, single-use manufacturing equipment, and a reliable source of donor cells is essential. Notably, donor cells must not introduce any chromosomal abnormalities.18,19
A typical harvest goal for an allogeneic cell therapy batch is 1011–1014 cells,20 and all those cells must be consistent in terms of their properties and quality. Producing such a quantity of cells with the same high level of cellular integrity and functionality can be difficult. Extended expansion of cells to the degree required can introduce differentiated phenotypes and possibly lead to T cell exhaustion or progressive loss of effector function and memory potential.21 Ensuring that all the cells have successfully undergone gene editing must also be achieved.22
Much effort is focused on overcoming these various challenges to the commercialization of allogeneic CAR-T cell therapies. Gene editing is thought to provide one of the best approaches to eliminating GvHD. Technologies such as CRISPR-Cas9 editing are being used to knock out specific genes that lead the expression of molecules that generate immune responses.2,4 Other options include the use immune-privileged mesenchymal stem cells (MSCs)23 and other immune cell types, such as virus-specific T cells, memory T cells, genetically modified αβ T cells, γδ T cells, and natural killer cells.2
Donor cell quality can be addressed if manufacturers partner with recognized suppliers that have demonstrated experience in gaining access to reliable, healthy allogeneic donors.24 Developing specifications for starting T cell populations and standards for apheresis equipment, procedures, and training should be a focus of the industry as well.
The potential advantages of allogeneic cell therapy are reflected in the shift occurring the in CAR-T cell therapy pipeline. GlobalData reported that, in January 2022, 542 CAR-T cell agents were in development, 59% of which were in preclinical or early clinical stages. Notably, the percentage of early-phase allogeneic candidates has increased measurably.14
Selected companies advancing allogeneic CAR-T cell therapies include Allogene, Adaptimmune (partnered with Genentech), CRISPR Therapeutics (collaborations with Bayer, Vertex Pharmaceuticals, KSQ Therapeutics, and others), Servier (licensed from Cellectis), Precision Biosciences, and Altara Biotherapeutics.14
Reports from these and other companies suggest that on average one batch equates to approximately 100 doses. Compared with autologous CAR-T cell therapies, therefore, the number of patients that can be treated per batch could be increased by 50–100 times, depending on the number of doses required.
Memorial Sloan Kettering Cancer Center. N.d.
Dr. Challener is an established industry editor and technical writing expert in the areas of chemistry and pharmaceuticals. She writes for various corporations and associations, as well as marketing agencies and research organizations, including That’s Nice and Nice Insight.