Regulatory T cell therapies at a translational crossroads

Prof Rita Carsetti, International Union of Immunological Societies, Germany, and Prof Michael Schmueck-Henneresse, University Health Network, Canada — Bringing tolerance-restoring Treg therapies to patients worldwide requires regulation, manufacturing, and reimbursement to evolve alongside the science.

DOI: https://doi.org/10.25453/plabs.32896283

Published on July 6th, 2026

The 2025 Nobel Prize in Physiology or Medicine highlights the profound impact of discoveries that have transformed our understanding of immune tolerance (1). Building on these discoveries, advances in Treg biology over the past three decades have progressed from fundamental mechanistic insights to the development of increasingly sophisticated cellular therapies. Early clinical trials have demonstrated safety and provided encouraging evidence of efficacy across transplantation, autoimmune diseases, and inflammatory disorders (2, 3, 4).More recently, the acceptance by the United States Food and Drugs Administration (FDA) of the first Biologics License Application for a Treg-based product marks an important milestone for the field and signals a transition from experimental therapy toward clinical implementation (5,6).  

This progress reflects a broader shift in medicine. Treg-based therapies are being developed not simply to suppress inflammation, but to restore immune tolerance and potentially achieve durable disease control, as Bluestone et al. describe in their Frontiers in Science lead article (1). These authors highlight how advances in Treg biology and engineering are transforming tolerance restoration from a scientific aspiration into a realistic therapeutic strategy (1). As these therapies approach regulatory and commercial milestones, the central challenge is no longer whether Treg therapies can work, but whether healthcare systems are prepared to support their widespread implementation. Addressing this challenge will require coordinated efforts across manufacturing, regulation, reimbursement, and translational innovation. 

Manufacturing for scale rather than proof-of-concept 

The first generation of Treg therapies was successfully developed within highly specialized academic centers using labor-intensive manufacturing processes (2, 3, 4).While these approaches established proof-of-concept and demonstrated safety in early clinical studies, broad implementation will require scalable and standardized manufacturing platforms. Advances in cell processing, automation, cryopreservation, and quality control are already improving reproducibility and reducing manufacturing complexity. At the same time, the field must balance innovation with practicality. While engineered products such as chimeric antigen receptor (CAR)-Tregs offer increased antigen specificity and opportunities to tailor Treg function to specific disease settings (7, 8), polyclonal Treg products remain attractive because of their simpler manufacturing, lower cost, and increasing clinical maturity. 

Different clinical indications may ultimately require different levels of product complexity, but all will depend on robust and scalable manufacturing infrastructure. Importantly, manufacturing challenges extend beyond scale alone. Unlike cytotoxic cell therapies, the potency of Treg products may depend not only on cell number and viability, but also on lineage stability, persistence, and the maintenance of suppressive function over time (9)). Standardized approaches to assessing these attributes remain an important unmet need for the field. Investment in manufacturing capacity should therefore be viewed not simply as a technical requirement but as a prerequisite for patient access. As the field matures, manufacturing considerations are increasingly becoming determinants of access rather than merely technical aspects of product development. 

Regulatory frameworks for living medicines 

Treg therapies challenge traditional regulatory paradigms. Unlike conventional pharmaceuticals, these products are living medicines whose effects may persist long after administration and whose mechanisms of action depend on dynamic interactions with tissues and the immune system. Indeed, the ultimate goal of many Treg therapies is not simply disease control, but the establishment of durable immune tolerance that may persist long after treatment has ended (10). Current regulatory frameworks for advanced therapy medicinal products have enabled important progress, but differences in manufacturing requirements, potency testing, and long-term follow-up expectations across jurisdictions continue to complicate global clinical development (11). 

Future regulatory efforts should focus on greater international harmonization, streamlined pathways for multicenter studies, and the development of regulatory approaches that recognize restoration of immune tolerance as a meaningful therapeutic endpoint. This may require regulators to consider outcomes such as durable drug minimization, operational tolerance, or long-term disease remission, which differ substantially from the endpoints traditionally used for many other advanced cellular therapies (2, 4). Equally important will be the establishment of robust long-term follow-up programs capable of capturing safety, durability, and real-world effectiveness. 

Rethinking value and reimbursement 

Many healthcare systems remain organized around chronic treatment paradigms in which therapies are administered continuously over years or decades. In contrast, many Treg therapies are being developed with the goal of reducing or eliminating the need for lifelong immunosuppression by establishing durable immune tolerance (4, 10). This shift creates important challenges for health technology assessment and reimbursement frameworks, which may not adequately capture the value of interventions designed to establish long-term immune tolerance. This challenge is particularly relevant for Treg therapies, whose ultimate value may lie not only in controlling disease activity but also in preventing the long-term toxicities, infections, malignancies, and healthcare costs associated with lifelong immunosuppression. As with other advanced cellular therapies, costs are likely to be concentrated upfront while benefits may accrue over many years (12, 13). Innovative reimbursement models, long-term outcome registries, and international data-sharing initiatives may therefore be required to appropriately assess the value of tolerance-restoring therapies. Policymakers should also consider equity from the outset. Without deliberate planning, access to advanced Treg therapies may initially be restricted to specialized centers and well-resourced healthcare systems, potentially widening existing disparities in access to innovative medicines. 

Sustaining translational ecosystems 

The remarkable progress of Treg therapies has been made possible through sustained collaboration between academia, industry, regulators, patient organizations, and public funders. Continued success will depend on preserving and expanding these partnerships. Academic investigators have generated the fundamental biological insights underpinning the field, while industry has played a critical role in manufacturing innovation, clinical development, and commercialization. The next phase of implementation will require even closer collaboration across sectors to ensure that scientific advances are translated into accessible therapies. Policies that encourage public-private partnerships, support translational infrastructure, and facilitate international cooperation will accelerate the development and deployment of safe, effective, and scalable Treg-based medicines. 

Conclusion 

Treg therapies now stand at a translational crossroads. Ensuring that regulatory frameworks, manufacturing infrastructure, and reimbursement systems evolve alongside scientific innovation will be essential if these therapies are to achieve their full potential for patients worldwide. Achieving this goal will likely require Treg-specific potency metrics, regulatory pathways that recognize restoration of immune tolerance as a meaningful therapeutic endpoint, and reimbursement models aligned with long-term clinical benefit. 

Copyright statement 

Copyright: © 2026 [Carsetti]. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution, or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in Frontiers Policy Labs is cited, in accordance with accepted academic practice. No use, distribution, or reproduction is permitted that does not comply with these terms.    

Generative AI statement
The authors declared that generative AI was not used in the creation of this manuscript.   

References 

1. Bluestone JA, Levings MK, Ramsdell FJ, Rudensky AY, Tang Q, Trzonkowski P. Regulatory T cells: master orchestrators of immune tolerance and tissue homeostasis. Front Sci (2026) 4: 1792210. doi: 10.3389/fsci.2026.1792210

2. Sawitzki B, Harden P, Reinke P, Moreau A, Hutchinson J, Game D, et al. Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet (2020) 395(10237):1627–39. doi: 10.1016/S0140-6736(20)30167-7 

3. Roemhild A, Otto NM, Moll G, Abou-El-Enein M, Kaiser D, Bold G, et al. Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial. BMJ (2020) 371:m3734. doi: 10.1136/bmj.m3734

4. Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology (2016) 64(2):632–43. doi: 10.1002/hep.28459 

5. Meyer EH, Salhotra A, Gandhi AP, Pantin J, Patel SS, Hoeg RT, et al. Orca-T vs allogeneic hematopoietic stem cell transplantation (PRECISION-T): a multicenter, randomized phase 3 trial. Blood (2026) 147(11):1168–77. doi: 10.1182/blood.2025031313 

6. Orca Bio. Orca Bio announces positive results from the pivotal phase 3 study of investigational Orca-T® compared to allogeneic stem cell transplant for the treatment of hematologic malignancies [online] (2025). Available online at: https://orcabio.com/orca-bio-announces-fda-review-extension-of-bla-for-orca-t-for-the-treatment-of-hematologic-malignancies/ 

7. Wardell CM, Fung V, Chen E, Haque M, Tan D, Leca M, et al. CAR T(reg) cells mediate linked suppression and infectious tolerance in islet transplantation in mice. Sci Transl Med (2025) 17(812):eadp6519. doi: 10.1126/scitranslmed.adp6519 

8. Wardell CM, Boardman DA, Levings MK. Harnessing the biology of regulatory T cells to treat disease. Nat Rev Drug Discov (2025) 24(2):93–111. doi: 10.1038/s41573-024-01089-x 

9. Wendering DJ, Amini L, Schlickeiser S, Farrera-Sal M, Schulenberg S, Peter L, et al. Effector memory-type regulatory T cells display phenotypic and functional instability. Sci Adv (2024) 10(36):eadn3470. doi: 10.1126/sciadv.adn3470 

10. Ho P, Cahir-McFarland E, Fontenot JD, Lodie T, Nada A, Tang Q, et al. Harnessing regulatory T cells to establish immune tolerance. Sci Transl Med (2024) 16(738):eadm8859. doi: 10.1126/scitranslmed.adm8859 

11. Pikor LA, Arivazhagan S, Mendicino M, Sathiamoorth S. Navigating the manufacturing, testing and regulatory complexities of regulatory T cells for adoptive cell therapy. Front Immunol (2025) 16:1626085. doi: 10.3389/fimmu.2025.1626085 

12. Jönsson B, Hampson G, Michaels J, Towse A, Graf von der Schulenburg JM, Wong O. Advanced therapy medicinal products and health technology assessment principles and practices for value-based and sustainable healthcare. Eur J Health Econ (2019) 20(3):427–38. doi: 10.1007/s10198-018-1007-x 

13. Gonçalves E. Value-based pricing for advanced therapy medicinal products: emerging affordability solutions. Eur J Health Econ (2022) 23(2):155–63. doi: 10.1007/s10198-021-01276-2