Over thirty years ago, Jeff Bluestone, PhD, and Fred Ramsdell, PhD, began pursuing a question: how does the immune system learn tolerance? In other words, how does it know when to stop attacking?

The answer lies in regulatory T cells (Tregs), immune cells that suppress the immune response to prevent overactivity, autoimmunity, and chronic inflammation. Because of this discovery, our knowledge of immune regulation has changed as a result of decades of research on immune system tolerance, and, for it, Ramsdell became a Nobel Laureate in Physiology or Medicine just weeks ago.

But Bluestone and Ramsdell’s story is more than just academic discovery; it is a story of patient-centered translation, from the lab bench to the first human therapies at Sonoma Biotherapeutics, which they co-founded—and now they have their first in-human proof.

At the 2025 American College of Rheumatology (ACR) Convergence, Sonoma Biotherapeutics presented early clinical data that signal a potential breakthrough in treating autoimmune disease. REGULATE-RA, the first human study of SBT-77-7101—an engineered CAR Treg cell therapy—for difficult-to-treat rheumatoid arthritis (RA), shows that the drug is safe and well-tolerated with no serious side effects. Early data indicate promising efficacy, with most participants experiencing substantial reductions in swollen joint counts and disease activity scores within four weeks of treatment, deeper responses at higher doses, and evidence of local anti-inflammatory effects in synovial tissue.

For Ramsdell, seeing Treg therapy produce tangible patient benefits is deeply validating. “This is really advanced disease in these patients, so it’s a pretty high bar,” Ramsdell told Inside Precision Medicine. “The fact that we’re seeing the responses we are really gives me hope that this is going to be effective even in these kinds of patients. We’ve got a ways to go to have a Phase III result and a marketed drug, but the biology right now and the patients look really good.”

For the field of immunology, this work represents a paradigm shift: leveraging the immune system’s natural regulators rather than merely suppressing immune responses. It demonstrates how decades of basic science, combined with technological innovation, can produce therapies that are both elegant and transformative.

The genetic roots of autoimmunity

In the early 1990s, Bluestone, then a young immunologist at the University of Chicago, was fascinated by one of immunology’s oldest mysteries: why the immune system sometimes attacks the body’s own tissues. Conventional wisdom had long focused on the immune system’s ability to destroy pathogens. But Bluestone’s lab began to reveal a subtler truth: the immune system also contains internal brakes, specialized T cells that restrain immune activation.

At the same time, Ramsdell, then a postdoctoral researcher, was studying a peculiar mouse strain that developed a fatal autoimmune disease caused by a previously mysterious gene. This gene, later identified as Foxp3, turned out to be the master regulator of Treg development. Bluestone, explaining the significance of Ramsdell’s work, said, “That genetic link gave hope that if we could figure out a therapeutic, it would be feasible.”

When the two scientists met, it became clear that they were circling the same problem from opposite directions: Bluestone was elucidating the immune system’s functional brakes, while Ramsdell was uncovering their genetic foundation. Ramsdell recalled, “When we first found this connection between Tregs and Foxp3, we postulated that if you could give cells, you could treat disease. It just took 20 years before that was possible… CAR T oncology played an important part, but we always knew it could be done.”

Translating Treg science into medicine

Conventional therapies for autoimmune diseases, such as corticosteroids or biologics, often rely on broad immune suppression. While effective for some patients, these approaches carry risks of infection, malignancy, and incomplete efficacy, because they do not selectively restore the immune system’s natural regulatory mechanisms.

Tregs provide a targeted approach, offering the possibility of durable immune recalibration rather than continuous suppression. For Ramsdell, the appeal of Tregs lies in leveraging nature’s own evolutionary design. “I don’t have to be smart if I use the right cell—Nature’s already done that for me,” said Ramsdell. “I was bullish 20–25 years ago and I’m just as bullish today because that logic still holds.”

But attempts to stimulate Tregs indirectly, such as with low-dose IL-2 regimens, have generated mixed results. “People have tried other ways to augment Treg biology,” said Ramsdell. “There have been studies with low doses of IL-2 or IL-2 mutants biased toward the CD25 receptor. Over time, there have been encouraging bits of data that that can work, but it hasn’t globally shown profound effects. In general, I don’t think it’s been a terribly successful strategy.”

By contrast, engineering Tregs allows for disease-specific targeting. “It’s a challenge because [IL-2] is a pan approach to all regulatory T cells,” Ramsdell said. “Whereas with engineering, we’re now able to focus our efforts on this particular thing. The long-term benefit is going to be the ability to focus the Treg on the disease where you want it to go.”

In 2019, Bluestone and Ramsdell co-founded Sonoma Biotherapeutics to bring this concept of CAR Treg cell therapies to patients. The biological foundation of Treg therapy gives Ramsdell confidence. “Tregs have been shown genetically and biologically to be powerful immune tolerance–inducing cells. That should translate into a broad set of activities. If the drug works, it’s likely to work in a lot of people.”

Ramsdell added, “With engineering, we can bias [Tregs] toward somebody’s disease while still bringing in the entire repertoire of function that these cells have.”

First-in-human trial of SBT-77-7101

The first proof of concept in humans comes from REGULATE-RA, a Phase I trial evaluating the safety, tolerability, and early efficacy of SBT-77-7101, a CAR Treg therapy, in patients with highly refractory RA. The trial includes three ascending dose cohorts and exploratory endpoints assessing pharmacokinetics, pharmacodynamics, mechanism of action, and early efficacy signals. 

Data from six participants—three in the lowest dose cohort (Cohort 1) and three in the medium dose cohort (Cohort 2)—showed that SBT-77-7101 is well-tolerated, with no dose-limiting toxicities, cytokine release syndrome (CRS), or immune effector cell-associated neurotoxicity syndrome (ICANS).

By Week 4, four of six participants (67%) achieved ≥50% reduction in swollen and tender joints, and five of six (83%) showed reductions in DAS28-CRP and CDAI scores. Notably, Cohort 2 participants, who received the higher dose, exhibited deeper and more consistent improvements, including one participant with a durable response through Week 24. Post-infusion biopsies revealed reduced inflammatory scores, while CAR+ Tregs were detectable in synovial tissue and peripheral blood, indicating both local and systemic activity.

Bluestone highlighted the patient impact: “Effectively in all inflamed patients, we’ve seen a dramatic reduction in disease activity… patients have had a very profound response, including opening jars for the first time in years or hiking up a 7,000-foot mountain near San Francisco. It’s a profound result.”

From a biological perspective, the trial also confirmed that infused Tregs persist in circulation for at least 28 days, home to inflamed tissue, and reduce inflammatory biomarkers. This provides compelling evidence that engineered Tregs can act in a targeted and durable manner in humans.

Stratifying autoimmunity

Bluestone agreed that precision is key—not just in the product, but in patient selection. “We have to understand the key attributes of the product to make sure we’re always making the best product,” Bluestone said. “And secondarily, we have to understand the variability among the patients and which patients are likely to respond. It’s not going to be every patient with RA.”

Bluestone continued, “For me, the next big step is really to understand the biology and make sure we have the right drug going into the right patient at the right time. If we can tackle a common node that’s critical for a set of diseases and select patients based on that, I think we have a much better chance of having a successful drug.”

Bluestone and Ramsdell are the first to admit that this is still early. “We haven’t treated enough patients yet to have data sets that will allow us to start to stratify or think about what was true of this patient that responds real well, but not this patient,” Bluestone said. “We need numbers. We need deep omics to really figure out what these patients are.”

Ramsdell pointed out that this uncertainty is not unique to cell therapy: “No one can predict who’s going to respond to an anti-TNF, and that’s not for lack of effort in the last 25 years. People have looked really hard at this. I hope it will be better than that, and we’re certainly going to work at it.”

As Sonoma completes its Phase I program and prepares for Phase II, both scientists are looking ahead to the broader implications. Bluestone remains focused on advancing the core science. “We’re still at the end of the beginning here,” Bluestone said. “We have to demonstrate in a rigorous Phase II setting that these cells really do what we want them to do and the patients have a durable response. If we can get to that, then we’ll worry about the next generation.”

Ramsdell sees the same milestone as both culmination and beginning. “We knew these cells could do this,” he said. “It just took time—and the right technology—to make it real.”

A Nobel moment

In October 2025, Fred Ramsdell was awarded the Nobel Prize in Physiology or Medicine, along with Mary E. Brunkow and Shimon Sakaguchi, “for their discoveries concerning peripheral immune tolerance.” The award recognized the decades-long work on Tregs and their role in regulating the immune system’s destructive potential.

The timing of the announcement and the failure to get in touch with Ramsdell have already become legendary. Ramsdell was deep in backpacking, disconnected from his phone, when the Nobel committee struggled to reach him. Reflecting on giving his first talk since being awarded the Nobel, Ramsdell said, “One of the more gratifying things in my life was to talk about the work from 25 years ago… to see it go from theoretically feasible to actually feasible is amazing. It’s early days, but just to be at this point—it’s fantastic.”

Bluestone echoed the sentiment: “I lived day-to-day with imposter syndrome… Waking up at night asking, ‘What if this is all for nothing?’ For me, this is a relief…that maybe this can work. Our field needs hope, and this is a deep breath moment—at least we’re on the right path.”

The promise of Bluestone and Ramsdell’s work is, in fact, becoming real for patients. The data presented at ACR 2025 suggests that patients with RA who have tried therapy after therapy without success may consider CAR Treg therapy, which is already in its early stages of development and is improving mobility, comfort, and quality of life in ways that traditional therapies frequently cannot.

Not everyone believed that the engineered CAR Tregs would be successful, according to Bluestone. In speaking about REGULATE-RA, Bluestone said, “We’re looking at how we advance the program now into Phase II, specifically in this refractory population. Most folks didn’t think we’d see much of a response in these patients and move the program forward. We’re now actively completing enrollment in our third cohort.”

For Bluestone and Ramsdell, Sonoma Biotherapeutics is more than a company; it is a living continuation of a decades-long vision. Their work affirms a simple yet profound idea: the immune system’s power to destroy is matched only by its power to heal. And for patients living with autoimmune diseases, that idea may finally become reality.