Following three patient deaths and the indefinite pause of several clinical trials, the research community is re-evaluating the safety of chimeric antigen receptor (CAR) T-cell therapies for autoimmune conditions. Swiss drugmaker Novartis paused eight phase 2 and phase 1/2 trials of its autologous CD19-targeting product, rap-cel, after encountering fatal cases of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS).
In Plain English: The Clinical Takeaway
- What Happened: Drug developers paused clinical trials testing CAR T-cell therapy for autoimmune diseases like lupus after three participants developed a fatal, severe form of immune system overactivation called IEC-HS.
- The Mechanism: CAR T-cell therapy reprograms a patient’s own immune cells, but this can trigger a dangerous, sterile inflammatory cascade.
- The Outlook: While earlier studies showed promising results for lupus and sclerosis, investigators are now pausing to determine how to prevent this rare, life-threatening inflammatory reaction.
Novartis and Bristol Myers Squibb Pause Autoimmune Trials After Fatal Complications
On August 24, Novartis announced it had suspended eight phase 2 and phase 1/2 trials of an autologous CD19-targeting product named rap-cel. The therapy was designed to target autoimmune and neurologic conditions, including rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis, systemic sclerosis (SSc), and Sjögren disease. Three instances of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS)—every single one ending in the death of the patient—prompted the temporary halt.
In a formal statement, Novartis confirmed that the trials are on hold for the foreseeable future while the company collaborates with independent data monitoring committees and global health authorities. Following the Novartis announcement, Bristol Myers Squibb (BMS) implemented its own voluntary pause on clinical studies evaluating a rival CAR T-cell product, zola-cel, acting out of an abundance of caution according to a Reuters report.
These sudden halts stunned the research community. Earlier this year, cell therapies were hailed as a potential game-changing therapy for autoimmune conditions. For instance, a study published in January in Nature Medicine evaluated 24 patients—comprising 10 with SLE, nine with SSc, and five with idiopathic inflammatory myopathies—who received a single infusion of zorpo-cel after discontinuing immunosuppressive treatments. The trial reported that potentially serious adverse events were moderate or did not occur, and 22 of the participants achieved predefined efficacy endpoints, with nine of 10 SLE patients reaching remission.
Understanding the Biology of IEC-HS in Rheumatology
Originally identified as an oncology complication, IEC-HS has now emerged as a focal point in rheumatology research. IEC-HS is defined as a pathologic immune reaction featuring secondary hemophagocytic lymphohistiocytosis or macrophage activation syndrome, occurring either independently or as a worsening continuation of cytokine release syndrome.
“IEC-HS is a state of usually sterile inflammation where you have to intervene with immunosuppressive treatment regimens,” stated Georg Schett, MD, vice president of research and head of the department of medicine 3 at Friedrich-Alexander-Universität Erlangen-Nürnberg in Germany, during an interview with Medscape Medical News. Schett noted that the complication is rare in cancer patients—less than 5%—and does not appear to carry an intrinsically higher baseline risk in autoimmune disease populations.
Supporting these observations, a real-world study published in May in Cancers analyzed 301 adults treated with commercial CAR T-cell products for hematologic malignancies. Researchers identified IEC-HS in 14 individuals, yielding an overall incidence rate of 4.7%. Symptom onset occurred at a median of 10 days post-infusion, typically manifesting during ongoing CRS or shortly after its resolution.
| Product Name | Developer | Target Indications | Current Trial Status |
|---|---|---|---|
| Rap-cel | Novartis | Rheumatoid arthritis, SLE, lupus nephritis, SSc, Sjögren disease | Paused |
| Zola-cel | Bristol Myers Squibb | Not specified | Voluntarily paused |
| Zorpo-cel | Not specified | SLE, SSc, idiopathic inflammatory myopathies | Not specified |
Future Directions for Cellular Immunotherapy in Autoimmunity
As regulatory bodies and independent safety committees review the fatal safety events, investigators are working to determine what can be done to prevent this from happening. “I think this is an important moment in time for us,” Sayeef Mirza, MD, MPH, a hematologist/oncologist and cellular immunotherapy investigator at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, told Medscape Medical News. “I think we are very excited with the advent and the discoveries of how beneficial CAR T is for lupus and scleroderma and multiple sclerosis, which are kind of the first poster children of autoimmune disease, being successfully treated with CAR T-cell therapy. But with these types of toxic and fatal events, it’s a moment for pause to figure out what we can do as cellular therapists and hematologists and disease specialists.”
References
- Nature Medicine: Efficacy and safety of CAR T-cell therapy in autoimmune diseases.
- Cancers: Real-world incidence and kinetics of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome.
- Medscape Medical News: Autoimmune Researchers Seek Answers After CAR T-Cell Deaths.
