Novartis and Bristol Myers Squibb Halt CAR T Trials After Deaths
- On August 24, Novartis announced the suspension of eight clinical trials evaluating an autologous CD19-targeting CAR T-cell therapy known as rap-cel, following three patient deaths due to immune...
- The regulatory and clinical pauses were triggered by three fatal cases of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome among trial participants receiving rap-cel.
- Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome represents a severe inflammatory response characterized by features of secondary hemophagocytic lymphohistiocytosis or macrophage activation syndrome.
On August 24, Novartis announced the suspension of eight clinical trials evaluating an autologous CD19-targeting CAR T-cell therapy known as rap-cel, following three patient deaths due to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, medscape.com reported. The voluntary halts across phase 2 and phase 1/2 studies target autoimmune and neurologic conditions, including systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, systemic sclerosis, and Sjögren disease.
The clinical holds arrived as a sudden disruption to a field that gained significant momentum earlier in the year. Experimental chimeric antigen receptor T-cell therapies had emerged as a promising approach for severe autoimmune disorders following clinical successes in patients with lupus, scleroderma, and multiple sclerosis.
Novartis and Bristol Myers Squibb Halt Trials After Fatal Events
The regulatory and clinical pauses were triggered by three fatal cases of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome among trial participants receiving rap-cel. In a statement provided to Medscape Medical News, Novartis confirmed that studies involving the product 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 instituted its own voluntary pause on clinical trials testing zola-cel, a rival CAR T-cell therapy, out of an abundance of caution, according to Reuters reporting. Bristol Myers Squibb did not respond to inquiries seeking further comment on the study suspensions.
Researchers Examine the Mechanics of Cellular Therapy Toxicity
Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome represents a severe inflammatory response characterized by features of secondary hemophagocytic lymphohistiocytosis or macrophage activation syndrome. This pathology can develop independently or as an escalating continuation of cytokine release syndrome.
“IEC-HS is a state of usually sterile inflammation where you have to intervene with immunosuppressive treatment regimens,” Georg Schett, MD, vice president of research and head of the department of medicine 3 at Friedrich-Alexander-Universität Erlangen-Nürnberg in Erlangen, Germany, told Medscape Medical News. Schett noted that the complication occurs in fewer than 5% of cancer patients treated with CAR T-cells and appears similarly infrequent in autoimmune applications, suggesting no inherent elevation in baseline risk for autoimmune cohorts.
Previous Studies Show Manageable Safety Profiles
Prior to the recent fatalities, published data from other similar investigations reported manageable safety profiles. A study published in January in Nature Medicine evaluated 24 patients treated with a distinct CAR T-cell product named zorpo-cel, which was not included in the paused trials. That study observed that cytokine release syndrome was moderate or absent, while immune effector cell-associated neurotoxicity syndrome did not occur, with 22 participants meeting predefined efficacy endpoints.
Sayeef Mirza, MD, MPH, a hematologist/oncologist and cellular immunotherapy investigator at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, emphasized the gravity of the current situation to 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. How can we work together to prevent this from happening?