In the high summer of 2026, the cell therapy field reached a historic milestone. The U.S. Food and Drug Administration (FDA) officially approved Orca Bio's precision-engineered cell therapy Tregzi for the prevention of chronic graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation for adults with high-risk hematologic malignancies such as leukemia.

 

This innovative therapy, which emerged from over two decades of technological development, has not only rewritten the fate of high-risk blood cancer patients for whom transplantation was once a gamble but has also thrust regulatory T cells (Tregs) from basic laboratory discoveries into the clinical spotlight, establishing yet another solid milestone in the cell therapy landscape.

 

TONACEA 01: The Past and Present of Treg Cell Therapy

 

Figure 1: 2025 Nobel Prize in Physiology or Medicine Laureates

 

On October 6, 2025, the Nobel Prize in Physiology or Medicine was awarded to American scientists Mary E. Brunkow and Fred Ramsdell, along with Japanese scientist Shimon Sakaguchi, in recognition of their foundational contributions to the study of regulatory T cells and the mechanisms of their key transcription factor FOXP3.

 

This honor not only crowned decades of fundamental immunology research but also injected strong academic momentum and public attention into the clinical translation of Treg therapies.

 

Figure 2: Academic Experts Driving Treg Industrialization Exploration

 

The industrial path of Tregs, however, was not achieved overnight.

 

At the turn of the century, the academic community gradually recognized the central role of Tregs in maintaining immune homeostasis and suppressing excessive inflammation, and began attempting to apply them to autoimmune diseases, transplant rejection, and GVHD.

 

In 2016, Dr. Sakaguchi pioneered RegCell, focusing on epigenetically reprogrammed antigen-specific Tregs to rebuild immune tolerance in patients. In 2019, fellow Nobel laureate Dr. Ramsdell, together with Treg authorities Professors Rudensky and Bluestone, co-founded Sonoma Biotherapeutics, representing the technology of polyclonal Treg expansion and reinfusion.

 

Driven jointly by academic giants and industry pioneers, global Treg therapy experienced a brief but intense wave of R&D enthusiasm. By early 2026, over 200 clinical trials around Treg therapies had been initiated, covering a wide range of autoimmune and inflammatory diseases including GVHD, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease.

 

TONACEA 02: From Ideal to Reality

 

While Tregs are theoretically endowed with multiple attractive advantages as "living drugs" — such as competitively consuming IL-2 to inhibit effector T cell (Teff) survival, suppressing antigen-presenting cell function, secreting anti-inflammatory cytokines like IL-10 and TGF-β, and even promoting tissue repair through growth factor secretion — clinical exploration has consistently failed to replicate this theoretical promise.

 

The reasons for this predicament are rooted in the deep contradictions between Treg biology and industrial-scale production.

 

First, manufacturing and purification barriers are high. Human Tregs lack a single specific surface marker. Relying solely on CD25 for sorting risks contamination with activated effector T cells (Teffs), which would pose uncontrollable safety risks upon reinfusion.

 

Second, cell expansion and phenotypic stability are problematic. Thymus-derived natural Tregs (tTregs) are extremely scarce in peripheral blood, making expansion time-consuming and labor-intensive. Meanwhile, in vitro-induced iTregs show insufficient stability in inflammatory microenvironments, and during expansion, Tregs often lose key chemokine receptors such as CCR7 and CD62L, significantly impairing their homing capacity.

 

More critically, in complex in vivo inflammatory environments, Tregs may undergo "lineage drift," not only losing the core transcription factor FOXP3 but even transdifferentiating into pathogenic effector cells, causing therapeutic misfocusing or even disease exacerbation.

 

Faced with these dilemmas, domestic and international companies have sought differentiated breakthroughs.

 

PolTREG expanded polyclonal Tregs in vitro, attempting early intervention in high-risk type 1 diabetes populations to delay disease progression. Cellenkos utilized umbilical cord blood-derived stem cells to generate "off-the-shelf" Tregs in vitro. Companies like Quell and Sonoma used gene editing to endow Tregs with chimeric antigen receptors (CARs) or antigen-specific TCRs, aiming to lock FOXP3 expression in vivo and enhance tissue homing.

 

However, the clinical efficacy of these strategies still awaits large-scale validation, while high production costs and complex manufacturing processes have cast a shadow over commercial feasibility and patient accessibility.

 

TONACEA 03: The Success Code of Tregzi

 

Amid these numerous difficulties, how did Orca Bio manage to stand out and ultimately secure FDA approval? An in-depth analysis of its R&D journey and clinical data reveals five key success factors.

 

1. Anchoring on Unmet Clinical Needs with Continuous Product Iteration

 

Orca Bio and the Stanford team consistently focused on the core pain point of high-risk complications following leukemia stem cell transplantation. Initially, to prevent early post-transplant relapse, the team attempted to co-infuse conventional T cells (Tconv) alongside CD34+ hematopoietic stem cells to exert an anti-leukemia effect. However, this strategy unfortunately triggered severe GVHD.

 

To strike a balance between "anti-leukemia" and "curbing immune overreaction," the team creatively introduced Tregs in 2002, ultimately forming a "CD34+ stem cells + Tconv + Treg" triple combination administration model, opening up a new approach to immune balance.

 

2. Disrupting Traditional Manufacturing Pathways to Circumvent Treg Expansion Hurdles

 

In vitro Treg expansion is time-consuming, costly, and prone to phenotypic instability — a recognized bottleneck in the industry. Orca Bio took a different path, employing a leukapheresis-based process. During CD34+ stem cell collection from donors, because T cells share the same density as CD34+ cells, both are simultaneously isolated. The procedure processes up to 30L of donor whole blood (approximately six times the adult blood volume), but most of the remaining components are safely returned to the donor, while Tregs are fully retained.

 

This design completely eliminates the need for in vitro expansion, shortening the "vein-to-vein" manufacturing cycle to an astonishing 72 hours, while obtaining a remarkably large quantity of Tregs (reaching 1–3 × 10⁶ /kg body weight).

 

3. Meticulously Refining Infusion Parameters with a Staggered Dosing Strategy

 

Orca Bio conducted multiple rounds of rigorous preclinical and clinical validation around infusion timing, dosage, and cryopreservation conditions. Animal studies showed that early infusion of lower Treg quantities prior to GVHD induction could effectively suppress the disease. Phase I trials further revealed that cryopreserved Tregs were paradoxically associated with severe GVHD; only high-purity fresh Tregs combined with a single-agent GVHD prophylaxis regimen demonstrated ideal feasibility and safety.

 

The final approved regimen therefore employs a sophisticated staggered design: approximately 10¹⁰ CD34+ cells, 10⁹ Tregs (doubly purified via CD25⁺ and CD127⁻), and an equivalent quantity of Tconv are co-isolated from the donor. Three days before transplantation, patients first receive fresh Treg infusions; three days later, they receive the cryopreserved CD34+ stem cells and Tconv. This staggered administration allows Tregs to establish an immunological regulatory high ground first, achieving preferential expansion and thereby greatly enhancing GVHD suppression efficacy.

 

4. Robust Proof-of-Concept Validation with Visual Data to Conquer Regulators

 

In early allogeneic bone marrow transplantation models, the team used bioluminescence imaging for long-term, non-invasive tracking of Tregs in mice, conclusively demonstrating that Tregs first expand in secondary lymphoid organs and then effectively migrate to inflamed tissues. In clinical trials, using immunomagnetic beads combined with high-speed cell sorting, the research team successfully isolated ultra-high-purity Tregs at 91%–96% purity.

 

Results showed that patients receiving fresh Tregs experienced neither acute nor chronic GVHD, while their post-transplant immune reconstitution levels were comparable to conventional transplant patients without GVHD, and risks of bacterial and viral infections were not increased — both safety and efficacy were validated.

 

5. The Pivotal Phase III PRECISION-T Trial Delivering Hard-Hitting Results

 

The FDA approval was primarily based on this randomized controlled trial involving 187 high-risk hematologic tumor patients. Data showed that the Tregzi group achieved a 1-year chronic GVHD-free survival rate of 78%, compared to only 38.4% in the standard transplant group. The incidence of severe chronic GVHD plummeted to 12.6% in the Tregzi group, while the control group registered a staggering 44%.

 

Even more encouraging, overall survival (OS) rose from 83% in the control group to 94%, an absolute improvement of 11 percentage points. Based on such significant clinical benefit, the FDA not only approved Tregzi for high-risk hematologic tumor patients but also granted it Orphan Drug Designation, establishing an institutional foundation for subsequent market exclusivity and pricing strategy.

 

Figure 3: Patients receiving Orca-T achieved 78% GVHD-free survival at one year post-transplant, compared to 38.4% in the control group.

 

Figure 4: One year post-transplant, the incidence of moderate-to-severe chronic GVHD was 12.6% in the Orca-T group, compared to 44.0% in the control group.

 

Figure 5: Patients receiving Orca-T had increased numbers of peripheral T cells to control relapse and infection, as well as increased Tregs to suppress GVHD.

 

Figure 6: The cumulative incidence of Grade 3 infections was lower in the Orca-T group (8.4% vs. 16%).

 

TONACEA 04: Treg Therapy Exploration in China

 

In China, Treg cell therapy has also attracted extensive attention from both academia and industry. Although starting somewhat later, the landscape is becoming increasingly diverse.

 

For example, Shanghai Cellevin Biotech, led by Dr. Lv Mingqi, innovatively uses intrathecal injection to deliver Tregs to the central nervous system for the treatment of amyotrophic lateral sclerosis (ALS). This strategy offers a highly imaginative approach to overcoming the tissue homing limitations of Tregs and has now advanced to the clinical stage.

 

Prof. Shi Yan of Tsinghua University founded Bodi Hekang, which took a different route. Targeting the fundamental bottleneck of Treg scarcity (only about 5% of peripheral T cells), the company independently developed an in vitro engineering editing technology that converts conventional Tconv obtained from a single venous blood draw into sufficient quantities of "Treg-like cells" (Enforce T). These engineered cells can exert Treg-like immunosuppressive functions from the outset while maintaining highly stable phenotypic characteristics, effectively circumventing the functional instability of traditional expanded Tregs and offering a new paradigm for scalable production and standardized quality control.

 

In addition, companies such as Meina Zhixin, founded by Dr. Su Yanjing, and Binuoji, led by Academician Dong Chen, have emerged, entering the Treg arena through different technological paths, covering autoimmune diseases, transplant immunology, and other indications. The domestic Treg industry map is becoming increasingly rich.

 

TONACEA 05: The Duet of Small Molecules and Biologics

 

Beyond in vitro cell therapies, strategies for directly inducing or expanding Tregs in vivo have also achieved notable breakthroughs in recent years, becoming another force in the Treg arena that cannot be ignored.

 

Figure 7: Diversity and technical classification of Treg therapies today

 

Currently, low-dose IL-2 is one of the most clinically validated in vivo induction strategies. The logic is simple yet elegant: Tregs highly express the IL-2 receptor (CD25), and extremely low concentrations of IL-2 can selectively activate and expand Tregs without stimulating effector T cells or NK cells.

 

Nektar Therapeutics' core pipeline, rezpegaldesleukin (REZPEG, i.e., NKTR-358), is a PEGylated biased IL-2 designed to durably and precisely enhance Treg function. In clinical trials for atopic dermatitis and alopecia areata, REZPEG has demonstrated significant efficacy, with long-term follow-up data further confirming its favorable safety profile and durable response, and it is now steadily advancing to Phase III.

 

Figure 8: NEKTAR's in vivo Treg induction technology has successfully opened the door to autoimmune indications

 

In China, Bodi Hekang, building on the deep expertise of Prof. Shi Yan's team at Tsinghua University's Institute of Immunology in oral immune tolerance, has developed the small molecule drug candidate BT-101. Its mechanism of action is unique: by activating a key receptor GPRx on intestinal dendritic cells (DCs), it promotes DC migration to mesenteric lymph nodes, thereby inducing the generation of peripheral regulatory T cells (pTregs) and re-establishing immune tolerance to self-antigens.

 

Based on this platform, BT-101 has demonstrated superior efficacy and favorable safety in preclinical colitis models, with potential for expansion to multiple indications including asthma, multiple sclerosis, and IgA nephropathy.

 

Currently, BT-101 has received clinical trial authorization from both China's CDE and the U.S. FDA and is actively advancing Phase I clinical studies, marking an important step for China in the field of in vivo Treg-inducing small molecule drugs.

 

— Conclusion —

 

After more than two decades of persistent dedication, Orca Bio has not only rigorously demonstrated through clinical evidence the powerful biological potential of Tregs in suppressing immune overactivation but has also successfully refined this insight into an innovative drug that can benefit patients. The approval of Tregzi will significantly reduce the risk of life-threatening chronic GVHD after stem cell transplantation, bringing genuine hope of a cure to countless leukemia patients struggling in desperate situations.

 

Looking ahead, Treg therapies are bound to enter a flourishing phase of "hundreds of schools of thought contending," yet deep challenges remain to be resolved: Treg mechanism research is still in a dynamic process of continuous correction and deepening; industrial project initiation for novel products must be built on profound insights into mechanisms of action; how to achieve tighter and more efficient integration between academic innovation and unmet clinical needs; how to truly implement standardized manufacturing processes, cost control, and commercial closure.

Drug development has never been a straight, unobstructed road, but a long, meandering journey through fog. Yet we believe that when basic research, clinical translation, and industrial innovation form a tighter positive feedback loop, Treg therapies will ultimately bring revolutionary therapeutic options for autoimmune diseases, transplant medicine, and even more inflammation-related conditions.

 

And this long journey, which began two decades ago, has only just opened its most exciting chapter.

 

Figure 9: Future prospects for Treg therapy