Novartis halts CAR-T trials after patient deaths
Novartis has paused eight clinical trials of its experimental CAR-T therapy rapcabtagene autoleucel (rap-cel or YTB323) after three patients died from a severe, life-threatening inflammatory condition.
The CD19-directed CAR-T, which uses the same CAR construct as Novartis' already-marketed Kymriah (tisagenlecleucel), but is a modified version that is quicker and easier to manufacture, is being tested for various autoimmune diseases, including rheumatoid arthritis, Sjögren's disease, systemic sclerosis, lupus, and various forms of multiple sclerosis.
The three patients died after developing a recognised complication of CAR-T therapy called immune effector cell-associated haemophagocytic syndrome (IEC-HS), in which the engineered immune cells multiply quickly and trigger a massive wave of inflammation leading to widespread organ and tissue damage. The complication has also been seen with some immune system-targeted bispecific antibody therapies.
Novartis confirmed that it halted screening, patient randomisation, and dosing across the affected clinical trials, all in the immunology and neuroscience area, on 24th August, but is continuing studies in cancer indications including high-risk large B-cell lymphoma. It has launched "a comprehensive review of the observed safety events" to determine whether the trials can resume.
BMS plays it safe
Meanwhile, Bristol Myers Squibb announced that it has also voluntarily paused enrolment in clinical trials of its own CD19-directed CAR-T zolacabtagene autoleucel (zola-cel or BMS-986353) in autoimmune diseases out of an "abundance of caution."
While stressing that it has not seen any deaths in its study programme, BMS did say it had seen evidence of "transient and reversible" inflammatory reactions in its trials of zola-cel.
Zola-cel is also a new construct based on the CD19-targeted CAR used in BMS' Breyanzi (lisocabtagene maraleucel) that has been designed for easier manufacturing, leading to speculation that the rapid production processes may be linked to the side effect. The CAR-T is being developed for lupus, systemic sclerosis, myositis, as well as for B-cell cancers like non-Hodgkin lymphoma (NHL).
CAR-T therapies have transformed the treatment of some serious blood cancers, but in the early days of their rollout were associated with serious and life-threatening adverse reactions like cytokine-release syndrome (CRS), which were eventually brought under control using pre-treatment medications and careful patient management and monitoring.
