Will Patient Deaths Derail the CAR-T Train in Autoimmune Disease?

Two Big Pharma companies have reportedly paused their ongoing trials of chimeric antigen receptor (CAR) T-cell therapies in lupus and other autoimmune inflammatory diseases after some participants suffered severe adverse events, including three deaths.

Novartis is said to have stopped enrollment and treatment in its trials of rapcabtagene autoleucel (rap-cel) in the wake of three fatal cases of immune effector cell-associated hemophagocytic syndrome (IEC-HS). Meanwhile, Bristol Myers Squibb (BMS) separately stopped its similar program involving zolacabtagene autoleucel (zola-cel) due to unspecified “transient and reversible inflammatory events.”

The suspensions were first reported late Monday by Fierce Biotech. Novartis didn’t respond immediately to an inquiry from MedPage Today; BMS provided a statement confirming the report but declined to provide further details.

ClinicalTrials.gov lists nine trials involving rap-cel across a wide range of autoimmune and other conditions: systemic lupus erythematosus (SLE), lupus nephritis, rheumatoid arthritis, Sjögren’s disease, systemic sclerosis, multiple sclerosis, myositis, and vasculitis, as well as two forms of hematologic cancer. BMS has three zola-cel trials listed targeting SLE, systemic sclerosis, and autoimmune cytopenia.

CAR T-cell therapy originated in oncology as a treatment for B cell-driven diseases such as lymphoma. Patients have T cells extracted and engineered in vitro to hunt down and kill rogue B cells. This has proved highly effective, and that success drew the attention of rheumatologists for its potential in autoimmune inflammatory conditions that also stem from abnormal B-cell activity. Results have been nothing short of astonishing, with long-lasting remissions seen in many patients who had failed every conventional therapy.

But the therapy is not entirely benign. It typically includes a relatively harsh conditioning regimen given prior to reinfusion of T cells. Some adverse events such as infections can be expected as a result, and the activated T cells can cause problems of their own. Cytokine release syndrome is common though usually mild and easily treated, but more severe immune-related problems can occur. A few cases of immune effector cell-associated neurotoxicity syndrome (ICANS) have been seen in rheumatologic patients.

Up to this point, however, IEC-HS has not been reported in those patients, although it’s a known, though rare, side effect in hematologic cancer applications: FDA-approved versions include a boxed warning about it, and numerous others not yet reported in autoimmune disease patients.

Fatal adverse events wouldn’t ordinarily doom a cancer drug. But in autoimmune diseases, which aren’t considered life-threatening (even though life expectancy may be reduced), that’s a different story.

BMS portrayed its halt as a relatively minor pothole in the road to market. In a statement to MedPage Today, the company said the adverse events emerged during “routine study surveillance.”

“To date,” it continued, “the overall safety profile of zola-cel remains consistent with the known profile of CAR T therapies. We are focused on completing our evaluation and resuming enrollment as quickly as possible.”

With the Novartis program and its three deaths, it will be important to know how many patients had been treated so far. One of the trials, in patients with SLE and/or lupus nephritis, has a planned enrollment of 179; for systemic sclerosis, 96; for vasculitis, 126; and another 60 or so in total for the other autoimmune trials. But those are the eventual targets and it’s unclear how far recruitment had progressed.