Point-of-care CAR T manufacturing solutions: can 1 model fit all?

One of the most important advances in the 21st century in the fight against cancer has been the development of chimeric antigen receptor (CAR) T cells in the treatment of acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Unfortunately, to date, access to this lifesaving therapy has been limited to very few patients worldwide. The reasons for this are, among others, their very high cost, the lack of interest of pharmaceutical companies in small or low–gross domestic product countries, the limited number of CAR T cells that can be prepared in a centralized manufacturing model, and the endemic slow incorporation of innovative, complex, and expensive treatments in many health systems. The pharmaceutical model of CAR T cells is focused on meeting the values of company shareholders, not filling the needs of patients who have no treatment options left. Here, we will detail the academic models looking to solve this dilemma.

Access to CAR T cells would be more equitable if they could be prepared in academic institutions, without the need for patient materials to be shipped and manufactured at centralized facilities. This model can be a realistic solution if an academic CAR T-cell platform can demonstrate successful and reproducible CAR T-cell manufacturing and noninferiority in terms of efficacy and toxicity compared with approved CAR T-cell therapeutics. To be sustainable, this platform needs to involve a network of hospitals, scientists, and physicians willing to collaborate in the preparation and administration of academic CAR T cells, with supervision of the network by a regulatory agency and the commitment to reimbursement of the academic CAR T-cell product. At the Hospital Clinic of Barcelona, a CD19 CAR T-cell product called ARI-001 for the treatment of patients with ALL and NHL and a BCMA CAR T-cell product called ARI-002h for patients with MM have been developed entirely through an academic network.¹ Both products have been rigorously tested in clinical trials after receiving authorization from the Spanish Agency for Medicines and Health Products (AEMPS). Clinical results have shown efficacy and toxicity to be very similar to CAR T cells prepared by industry or other academic institutions.^2,3 In this Spanish program, the lentiviral vectors used for the genetic modification of T lymphocytes were prepared in a Good Manufacturing Practices (GMP) clean room with controlled negative pressure (grade A-B). Transduced lymphocytes were expanded using the CliniMACS Prodigy by Miltenyi Biotec, installed in 2 GMP, grade C, clean rooms (reagents prepared in grade B).⁴ Grading system is based on the standard classification of air cleanliness by particle concentration (ISO 14644-1 nomenclature).

Spain has proven that an independent academic group can successfully meet the clinical needs of patients with NHL, ALL, and MM, with more than 360 patients with advanced disease now treated in Spain. The current production rate of ARI CAR T cells allows for a capacity of >100 patients per year. Currently, this meets the clinical demand of the Spanish patient population but will likely be insufficient in the future as disease indications for CAR T cells grow. For this reason, the Barcelona group has trained the cell therapy unit of the University of Navarra for the production of ARI CAR T cells. In both facilities (Hospital Clinic of Barcelona and University of Navarra), the same manufacturing procedures, analytical methods, reagents, and the same bioreactor were implemented. The comparison of quality controls has confirmed equivalent production in both centers.³ Soon, 3 other Spanish academic centers will begin the production of ARI CAR T cells to build the needed capacity.

For the sustainability of this academic CAR T-cell therapy network, the recognition and supervision of the AEMPS and the financial support (reimbursement) of the Ministry of Health were crucial. After a detailed review of the clinical results, the AEMPS authorized the use of ARI-001 in patients with relapsed or refractory (R/R) ALL older than 25 years of age (in Spain, tisagenlecleucel, from Novartis, is authorized for patients with R/R ALL younger than 25 years of age). This exceptional authorization was based on the so-called “hospital exemption” (HE),⁵ which allows for the use of advanced therapies in a country of the European Union (EU), without the need for prior approval by the European Medicines Agency (EMA). According to HE regulations, it is mandatory to periodically send patients’ clinical results to the AEMPS, including the results of quality controls, safety standards, and pharmacovigilance. The price of ARI-001, which is reimbursed by the Spanish Ministry of Health, is 89 000 euros (∼97 000 USD), significantly less than the advertised price of commercial CAR T-cell products. In relation to this cost, we have seen similar low price points in other jurisdictions related to academic CAR T-cell manufacturing, such as India.⁶ ARI-001 has now entered the EMA authorization request process for the eventual distribution of ARI-001 in the EU for patients with R/R ALL. This strategy would establish the first academically derived CAR T-cell product to reach market authorization in the EU and would build the foundation for other academic CAR T-cell products in Europe to reach patients in need, without the involvement of big pharmaceutical companies.

We have no doubt that many other institutions worldwide may develop effective and safe academic CAR T cells within clinical trials, under a point-of-care (POC) national network. Some examples worldwide have been recently summarized, which highlights Canada and Brazil in addition to the EU.⁷ The critical point is how to continue an academic program once the clinical trial is closed. For this, 2 aspects are key: fulfillment of local/national regulatory requirements and to achieve an agreement for reimbursement with health payers (either public or private). In principle, any country might put in practice a program such as the Spanish model if the payer is willing to reimburse cost, but expanding this beyond one country is tedious without harmonization of regulatory practices. This is perhaps a topic that the CAR T cell world leaders could advocate for, but this has not been done to date and would require countries to agree to one regulatory guideline, a strategy that is not likely straightforward. A proposal for the creation of a new American entity, called “Pediatric Advanced Medicines Biotech,”⁷ to lead late-stage development and commercialize cell and gene therapies outside the traditional biopharmaceutical model exemplifies how creative approaches increase accessibility to new treatments that can be led by academic networks. Perhaps this field needs more creativity among national and international academic bodies to bring more unified global solutions.

Although central manufacturing with a third-party pharmaceutical company dominates the US market, many of these advances were reliant on initial development of a construct and manufacturing process at a single institutional site. The best example is the approval of tisagenlecleucel, the first CD19 CAR T-cell product approved in the United States.⁸ The construct was first developed by scientists at the University of Pennsylvania with early dose finding and safety profile defined during phase 1 single-center investigator-initiated studies (IIS).^9,10 This asset was licensed later to Novartis¹¹ who led multiple global studies resulting in the approval of this agent for multiple indications in B-cell malignancies.^12,13 

Although such efforts were initially limited to larger academic centers with GMP compliant cell manufacturing facilities, advances in CAR manufacturing with tabletop systems that are fully closed (eg, CliniMACS Prodigy) have now democratized the ability to manufacture CAR T cells to most centers with cell therapy expertise.¹⁴ This has led to numerous clinical trials worldwide resulting in rapid CAR innovation through a series of phase 1 single-center trials.^15-18 Unlike pharmaceutical companies with competing interests and the burden to appease shareholders, academic centers are free to test novel concepts and can often initiate trials quickly generating early data to help support larger trials. Results of this work can then direct collaborations with pharmaceutical companies allowing them to focus on high value assets for multicenter approaches and registrational trials.

Several academic to industry collaborations have demonstrated the value of POC manufacturing to drive innovation followed by pharmaceutical support for multicenter phase 2 trials. The initial work for zamtocabtagene autoleucel, a first-in-class anti-CD20/anti-CD19 bispecific CAR, was performed at the Medical College of Wisconsin under a phase 1 IIS that both identified a safe dose for future trials and defined the manufacturing process for this product. Manufacturing was done using a POC process with the CliniMACS Prodigy with a fresh-in, fresh-out procedure to eliminate any cryopreservation step.¹⁵ This trial informed the development of 2 ongoing clinical trials in Europe and the United States (NCT04792489) using zamtocabtagene autoleucel in second- and third-line diffuse large B-cell lymphoma (DLBCL) with the same dose and noncryopreserved infusion detailed in the phase 1 single-center study. Similarly, the team at Stanford was key in the development of an anti-CD22 CAR construct for patients with relapsed DLBCL after CD19 CAR T-cell exposure. They too used the CliniMACS Prodigy for their manufacturing process and as part of a phase 1 IIS, identified a safe dose with promising efficacy in this difficult-to-treat population.¹⁷ Their work translated to a now multicenter phase 2 study (NCT05972720) led by CARGO Therapeutics with the anti-CD22 construct (firicabtagene autoleucel) for patients with progressive DLBCL after CD19 CAR T-cell therapy. In both cases earlier, the initial Investigational New Drug submission and phase 1 trial were performed by academic centers using a closed manufacturing system to produce CAR T cells for patients. These data then advised industrial partners on the design, safety, and dose to use for larger multicenter trials, which should allow these products to reach market authorization.

Although this work could have been done via industry, the cost of development and time needed to develop these trials via industry are likely not the most efficient model to test out numerous new constructs. Earlier, we have identified several examples of academic innovations expediting the development of cellular therapy products through industry, but an alternative model would be for academic centers to collaborate to develop phase 2/3 trials. Using existing networks such as the Bone Marrow Transplant Clinical Trials Network (BMT CTN) or the Pediatric Transplantation and Cell Therapy Consortium (PTCTC), it is possible to maintain the manufacturing of cell therapy products within academic centers. For example, large clinical trials that have modified standard of care in transplantation have occurred through BMT CTN without any industry support (posttransplant cyclophosphamide for graft-versus-host disease prophylaxis¹⁹). Similar efforts are ongoing in cell therapy. This includes an ongoing collaborative effort through the PTCTC to develop CD33 CAR T cells via a multicenter trial with centralized manufacturing occurring at the National Cancer Institute (not an industry partner, NCT03971799).²⁰ Whether this work can be translated to a registrational study remains a question, but through collaborations and commitment to a consistent process this remains a possibility.

Although it may appear that POC academic models are competing with pharmaceutical companies, a symbiotic relationship is plausible. CAR T-cell therapy in any model requires complex steps in manufacturing that include the transport of patient materials; supply chain processes; regulatory, contractual, and reimbursement hurdles to overcome; and specialized clinical care for CAR T-cell–related toxicities. Although pharmaceutical companies can easily support the market authorization and rollout of CAR T-cell therapeutics, this complexity related to CAR T-cell administration has created significant delays to clinical implementation and has widened the inequality of cancer care access.²¹ Building POC manufacturing infrastructure does not have to serve as a competition for pharmaceutical companies but can instead narrow the inequality gap that currently exists with commercial CAR T-cell programs. Despite growing experience with commercial CAR T-cell therapies, delays to reimbursement and access will remain for many years to come, as evidenced by the lack of availability of commercial CAR T cells for MM for much of the world despite regulatory approvals. Although industry can provide the infrastructure and investment needed for large-scale capacity and worldwide market authorization, academic networks are needed to foster the innovation in this field and consider the more sporadic disease entities that may not lead to the profit margins needed for pharmaceutical companies to invest.

For rare conditions where initial industry interest may be limited, an academic model of discovery is crucial to advancing the science.²² In Canada, the Canadian-Led Immunotherapies in Cancer (CLIC) program that uses centralized plasmid and lentiviral manufacturing with the previously described POC Miltenyi CliniMACS system for cell manufacturing created an academic network for Canadian CAR T-cell science to reach the clinic. This is an entirely academic network where vector, plasmid, lentivirus, and CAR T-cell manufacturing are all performed under 2 research institutes, with a plan to expand to more academic sites across the country, similar to the Spanish model. After developing a proof-of-principle CD19 CAR T-cell trial,²³ a novel CD22 single-domain camelid CAR T-cell product will enter the clinic using the CLIC network (NCT06208735). Although there are similarities to the Spanish and Indian academic programs, the Canadian program was built despite the existence of approved pharmaceutical CAR T-cell products in Canada. Although CLIC did bring access to patients with more rare CD19 tumors who did not fit the eligibility for commercial CAR T cells, it also constructed a pathway enabling Canadian CAR T-cell advancements to transition into clinical application, a crucial infrastructure for propelling CAR T-cell technologies forward. This allowed for the development of the CD22 CAR T cells but also CAR T-cell targets that would not have reached clinical trial without this network.

Although neither system is perfect, one that relies on industry and profit and another that relies on philanthropy, government grants, and academic collaboration, perhaps a model that incorporates both will lead this charge. “Middle ground” models such as Galapagos that focus on public need while relying on private investment may bring a needed solution, but it is too early to comment on the output of these models.²⁴ Collaboration between academic programs and industry can be jointly fruitful to rapidly bring to the field much needed therapies for patients in need. Further POC manufacturing models can and should be globalized to increase accessibility of cell therapy treatments beyond North America and Europe.

Contribution: N.N.S., A.U.-I., and N.K. equally wrote and edited the manuscript.

Conflict-of-interest disclosure: N.N.S. reports participation on advisory boards and/or consultancy for Gilead-Kite, Bristol Myers Squibb–Juno, Miltenyi Biomedicine, Lilly Oncology, Incyte, Novartis, Seattle Genetics, Janssen, AbbVie, CARGO, BeiGene, and Galapagos; has research funding, travel support, and honoraria from Lilly Oncology, Genentech, and Miltenyi Biomedicine; and is on a scientific advisory board for Tundra Therapeutics. N.K. receives honoraria and participates in advisory boards for Gilead-Kite. A.U.-I. declares no competing financial interests.

Correspondence: Natasha Kekre, Transplantation and Cellular Therapy Program, The Ottawa Hospital, 501 Smyth Rd, CPCR Box 201A, Ottawa, ON K1H 8L6, Canada; email: nkekre@toh.ca.