Charting the course for CAR T-cell manufacturing

In this issue of Blood Advances, Urbano-Ispizua et al¹ present 3 points of view on chimeric antigen receptor (CAR) T-cell manufacturing. First, point-of-care (PoC) manufacturing of CAR T cells could be the sole answer to ensuring equitable access to such transformative therapies. Second, the commercial centralized model for developing CAR T-cell therapies is crucial for upscaling and disseminating these treatments. Finally, a symbiotic relationship between centralized industry manufacturing and the academic PoC model could exist.

PoC creates an opportunity for equitable access to transformative therapies due to its easy-to-set-up workflow and the availability of reliable technology that allows for reproducible manufacturing of CAR T-cell products (see figure).^2,3 This is evident in the successful implementation of PoC manufacturing at institutional levels in different countries. Such implementation has now been achieved in India and is anticipated in Brazil, where the centrally manufactured CAR T-cell products have not yet reached the market.⁴ This highlights the power of the model in bringing CAR T cells to patients in need promptly. Equitable access is further supported by the fact that academic institutions would charge significantly less for these therapies compared with commercially available products.^4,5 However, for PoC manufacturing to extend beyond single institutions and become a widespread, sustainable approach, a change in policy by regulators and payers is needed. This approach is exemplified by the success of the product developed by the Hospital Clinic of Barcelona (ARI-001), which received support from both authorities and payers, resulting in the treatment of >360 patients to date and establishing a network of hospitals providing these products. Such success was possible based on the policy in place by the European Medicines Agency that allows for hospital exemption from market approval.⁵ In Canada, the Canadian-Led Immunotherapies for Cancer program has established an academic network to advance Canadian CAR T-cell therapies to the clinic. This initiative combines centralized plasmid and lentiviral vector production with PoC cell manufacturing, leveraging the Miltenyi CliniMACS system. Meanwhile, the United Kingdom is progressing toward the adoption of PoC manufacturing through a centralized regulatory framework overseen by the Medicines and Healthcare Products Regulatory Agency.³ 

The current global landscape indicates that the PoC model will need to be tailored to fit the regulatory, health care, and reimbursement structure for each country. Although this creates opportunities for some nations, it presents hurdles for others. In the United States, the current regulatory and reimbursement landscape may require more innovative approaches to enable access to products that have not found a path to commercialization. The authors highlighted that this approach could involve building upon more centralized entities that could organize and drive the development of PoC models. For testing PoC manufacturing at a multi-institutional level, trial consortia with experience in initiating clinical trials could be leveraged. The authors particularly point to 2 consortia: Bone Marrow Transplant-Clinical Trials Network and Pediatric Transplantation and Cell Therapy Consortium (PTCTC). The PTCTC is currently running a centrally manufactured multicenter CD33-based CAR T-cell trial, although it remains unclear whether this development will lead to the commercialization of the product.⁶ Another approach could be to establish an independent entity that can advance products that do not fall within the industry’s primary focus. A proposal has been put forward to establish a new non-for-profit or hybrid nonprofit/for-profit entity called “Pediatric Advanced Medicines Biotech” that can take charge of late-stage development and commercialize cell and gene therapies while operating independently from the conventional biopharmaceutical framework.⁷ This exemplifies how creative approaches can increase accessibility to new treatments through academic networks.

Finally, it is undeniable that the collaboration between industry and academia has helped progress several CAR T-cell products to patients. However, financial factors and shareholder pressure may interfere with the development of therapies for certain indications and patient groups. In such cases, there must be a pathway to continue development and access to cell-based products for unmet medical needs that might not have large-scale commercial viability. The PoC model provides this opportunity. It might also be in the best interest of the industry to support the PoC manufacturing model, because it has fueled the innovation and testing of different innovative CAR T cells and treatment strategies. The industry has historically benefited from this by licensing some of the products, and several innovations from PoC have inspired development strategies that were later adopted by the industry.⁸ There is also the opportunity for more patient-focused solutions from the industry; for example, the biotechnology company Galapagos recently started a collaboration with Blood Centers of America with the aim of implementing the PoC model at the industry scale.

Although PoC has been gaining traction as a solution for improving access and maintaining development for unmet medical needs, several open questions still exist. Further engagement across academic institutes, industry, regulators, and payers is much needed for the successful adoption of such a model).

Conflict-of-interest disclosure: M.V.M. is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab and Luminary) and University of Pennsylvania (some licensed to Novartis); receives grant/research support from Kite Pharma, Moderna, and Sobi; has served as a consultant for multiple companies involved in cell therapies; holds Equity in 2seventy bio, A2Bio, Affyimmune, BendBio, Cargo, GBM NewCo, Model T Bio, Neximmune, and Oncternal; and is in the board of directors of 2seventy bio. M.E. declares no competing financial interests.