Enhancing CAR-T Therapy: From Cancer to Autoimmune Diseases

A once futuristic-sounding cancer treatment that involves extracting a patient’s own immune cells, re-engineering them to recognize tumor targets, and returning them to the body is beginning to move beyond oncology.

At Yale School of Medicine (YSM), physician-scientists are testing CAR-T (chimeric antigen receptor-T cell) therapy in clinical trials for autoimmune diseases including lupus, multiple sclerosis (MS), and scleroderma. Meanwhile, YSM basic science researchers are focused on better understanding how CAR-T therapy works—and how it can be improved.

CAR-T therapy was first developed to treat blood cancers such as leukemia and lymphoma, and it has produced dramatic and sometimes long-lasting remissions in patients who have exhausted standard therapies.

“CAR-T therapy is what we call a living drug,” says Michael Hurwitz, MD, PhD, associate professor of medicine (medical oncology). “When it works well, those cells don’t just attack their target once, they expand, persist, and continue functioning in the body.”

Unlike long-term maintenance treatments, CAR-T therapy is typically delivered as a single infusion, though durability varies by disease and remains unknown for autoimmune diseases, which are driven by immune cells attacking the body’s own tissues.

“Many autoimmune diseases are caused by the immune system going rogue,” Hurwitz says. “If you can identify and eliminate the cells responsible, you may be able to reset the disease rather than simply suppress it.”

However, CAR‑T therapy’s power comes with risk. The therapy can trigger intense immune activation, including cytokine release syndrome (CRS)—an inflammatory reaction that may cause fever and low blood pressure—and, less commonly, neurologic side effects such as confusion. Because those reactions can escalate quickly, patients are monitored closely and treated using established protocols.

Since 2017, seven CAR‑T therapies have been FDA‑approved, all for blood cancers.

The process begins with collecting a patient’s immune cells via apheresis, an outpatient procedure that filters immune cells from the bloodstream. Those cells are genetically engineered and expanded in a laboratory over several weeks before being infused back into the patient.

An oncology-focused effort has grown into a broader, multidisciplinary Cell Therapy Program at Yale Cancer Center. Teams from hematology-oncology, rheumatology, and neurology have come together to study CAR-T therapy for MS, scleroderma, and lupus in clinical trials. The program launched in August 2025 when the first patient with MS received CAR-T cells. Earlier this year, Yale clinicians performed the first CAR-T infusion for lupus in the state.

Multiple sclerosis is an immune-mediated disease in which the body’s own immune cells mistakenly attack the brain and spinal cord, damaging the protective myelin that allows nerve cells to communicate. That immune-driven inflammation can trigger episodes of new or worsening symptoms, known as relapses, and, over time, contribute to neurological disability.

Treatment for MS has increasingly focused on B cells, immune cells that play a central role in driving inflammation and nerve damage by producing antibodies that mistakenly target the body’s own tissues. But while current B cell therapies can reduce relapses by clearing immune cells from the bloodstream, they do not always stop progression once inflammation becomes entrenched in the brain and surrounding tissues.

That limitation is central to the work of Yale’s Erin Longbrake, MD, PhD, associate professor of neurology and principal investigator of an early-phase clinical trial testing whether CAR-T therapy can eliminate disease-driving immune cells not only in the bloodstream, but throughout the body—including the brain.

CAR-T cells, unlike monoclonal antibody therapies, are living immune cells that have been genetically engineered to recognize a specific target. In non-oncology trials, including Longbrake’s study, the CAR-T cells are designed to recognize CD19, a marker found on B cells. Once infused back into the patient, those reprogrammed T cells seek out and destroy B cells wherever they are located.

“The monoclonal antibodies we use now do a very good job of clearing B cells from the blood, but they don’t effectively deplete B cells that are in tissues, and they don’t go into the brain,” Longbrake says. “A CAR-T cell doesn’t have those barriers.”

That difference helps explain why CAR-T therapy has drawn attention as a possible next step for patients whose disease continues to progress despite the most aggressive standard therapies.

“The big questions now are whether this actually changes the course of the disease, and in which patients,” Longbrake says. “These are very small numbers, but so far the safety profile has been encouraging. Still, we need to understand who this approach might help—and who it won’t.”

For now, CAR-T therapy remains firmly in the realm of early clinical research for MS, tested only in patients with the most treatment-resistant disease. Whether deeper immune depletion can translate into durable disease control—and whether the risks are acceptable—are questions that larger and longer studies will have to answer first.

The challenge of immune cells that persist despite treatment is not unique to MS. It also defines systemic autoimmune diseases like lupus, where immune-driven inflammation can affect multiple organs and remain difficult to fully suppress.

Like MS, lupus is driven in part by long-lived T and B lymphocytes that can persist despite treatment. Existing lupus therapies reduce inflammation and suppress antibody production, but they struggle to eliminate long-lived lymphocytes that reside deep in tissues and lymph nodes.

By targeting and removing those cells, researchers are looking to see if they can reset the immune system. Whether that kind of reset can translate into durable remission remains an open question—one that early CAR-T therapy trials in lupus and other autoimmune diseases are only beginning to explore.

With scleroderma, also known as systemic sclerosis, immune dysfunction can trigger inflammation, blood vessel damage, and progressive scarring in the skin and internal organs, especially the lungs. Current therapies can slow decline, but do little to restore function once fibrosis is established, says Monique Hinchcliff, MD, MS, associate professor of medicine (rheumatology) and director of the Yale Scleroderma Program.

“If we can put you on medicines that just maintain your lung function where you are, that’s a win,” Hinchcliff says. “But wouldn’t it be great if we could go beyond that and prevent lung function decline in patients with systemic sclerosis at high risk for progressive lung disease?”

For now, she adds, CAR-T therapy is being studied only in carefully selected patients at highest risk of progression, when disrupting immune system hyperactivity may offer the greatest chance of benefit.

As CAR‑T therapy moves into new clinical territory, Yale researchers are also focused on improving the therapy at the design level. Their goal is to make engineered immune cells more tunable—able to sense harder-to-detect targets, stay effective longer, and avoid the kind of overactivation that can drive toxicity.

For Xiaolei Su, PhD, assistant professor of cell biology, that design challenge starts with a basic observation: CARs are built to be modular. Su describes CAR as a “LEGO”-like receptor, with an external component that recognizes a target and internal signaling components that determine what the cell does next. That mix-and-match flexibility is part of what has allowed CAR-based approaches to expand from cancer into other disease areas as new targets come into view.

A major barrier, Su notes, is sensitivity. Compared with the T cell receptor, which T cells normally use to recognize targets, CARs generally require a stronger or more abundant signal before they fully activate. Standard CAR‑T cells can struggle when target markers are sparse—an issue that shows up in many solid tumors, where antigen expression varies cell to cell, and in tumors that adapt by dialing antigen expression down.

In recent preclinical work, Su’s lab developed a new engineering strategy that adds intrinsically disordered regions (IDRs) to the CAR, amplifying weak activation signals and improving killing against low‑antigen targets in laboratory and animal studies.

“We want to generate a toolbox of IDRs to meet the requests of different antigens because different types require various antigen sensitivity levels to best achieve balance,” Su explains.

Meanwhile, Sidi Chen, PhD, associate professor of genetics and of neurosurgery, treats cell therapy as a systems-level engineering challenge. His lab uses CRISPR-based genetic approaches to identify which genes shape immune-cell performance to improve persistence, potency, and safety.

One strategy from Chen’s group is to modify the CAR itself to help engineered cells last longer. By adding part of a natural immune “brake” protein called CTLA‑4 to the receptor, the team improved CAR‑T performance in preclinical leukemia studies.

Chen’s group has also pushed beyond CAR‑T toward other immune-cell platforms, including a way to work with a type of white blood cells called natural killer (NK) cells and make them more effective against cancer.

NK cells kill infected, damaged, or malignant cells in the body. CAR‑NK strategies aim to address hurdles in solid tumors, including poor infiltration and immune exhaustion, a worn-down state in which immune cells lose function after prolonged activation. Some CAR-NK approaches are also being explored as “off-the-shelf” therapies made from donor cells rather than manufactured from each patient’s own cells.

As the science advances, clinicians still must decide when—and for whom—this powerful approach makes sense outside of cancer. CAR‑T therapy may be among the most powerful tools medicine has developed, but it is also among the most complex.

“These are extraordinary therapies,” says Hurwitz, a team leader of the Cell Therapy Program. “But they require us to be very intentional—about who we treat, where we treat, and what risks patients are willing to accept.”

CAR‑T therapy is less like a conventional drug and more like a complex cellular procedure, explains Stuart Seropian, MD, professor of medicine (medical oncology and hematology) and director of Yale Cancer Center’s Stem Cell Transplant Program. Delivering it safely requires a coordinated transplant and cellular therapy infrastructure.

“It requires a program, not just a physician, to administer these treatments,” he says.

Because CAR‑T therapy can trigger intense immune activation, patients are monitored closely for inflammatory side effects such as fever and blood‑pressure changes and neurologic symptoms. Those reactions tend to correlate with tumor burden, Seropian notes.

“In autoimmune disease, that burden just isn’t there in the same way,” he says, which is one reason side effects have so far appeared more tolerable when used for autoimmune diseases.

Whether CAR‑T therapy will ultimately redefine treatment for autoimmune disease remains an open question. For now, the work unfolding at Yale reflects a broader shift in medicine—one that treats the immune system not as something to suppress, but as something that can potentially be reset.