What Does The Box Warning on Approved CAR-Ts Mean for New CAR-Ts?
(Thursday, January 25, 2024)
About 2 months after the first public reports of T-cell cancers linked to CAR-T therapies, the FDA finally decided to put a Box warning on all approved CAR-T therapies for unexpected malignancies. At the same time, the FDA also raised new expectations from CAR-T therapies in development, particularly those for indications outside hematology and oncology. While approved CAR-T therapies deal with this new box warning, the ones in development are likely in for a bigger hurdle to their clinical trials and FDA approval.
CAR-T therapies have been used to treat about 30,000 patients in the US and 50,000 worldwide for the treatment of B cell leukemia, lymphoma, and multiple myeloma. The CAR-T therapies are one of the most successful FDA-approved cellular therapies that have generated billions of dollars in revenue for its developers, attracting hundreds of other developers to this class of treatment. Currently, there are about 250 new CAR-T therapies under development in the US and another 500 in other countries, all vying for FDA approval in the coming years. The Box Warning could potentially create additional pre-approval requirements for these new therapies.
The risk of cancer with insertional gene therapy has been well-known for more than two decades. All CAR-T therapies use viral transduction to insert the gene of interest in the genome of the treated cells. The most popular viral system used for transduction is the lentiviral vector constructs. These vectors have an affinity for areas of the genome with active gene expression, which pose the risk of insertional oncogenesis. The ex-vivo transduction of T-cells followed by transplantation into the patients eliminates the risk of overall oncogenesis but does not address the risk of T-cell cancers, since these were the cells transduced with the viral vectors in the first place. The reports of T-cell cancers in patients treated with CAR-T therapies confirm this fear. The incidence rate of T-cell cancers is very low; there have been 22 reports of which 14 cases had confirmed colocalization of T-cell cancers and the CAR-T treatments. Since these reports came from voluntary post-market safety reports, the FDA believes that these numbers under-represent the true count of CAR-T-associated T-cell cancers. Hence, the FDA decided to require a mandatory boxed warning (the highest category of warning label for a drug), and other warnings on the product label for all CAR-T therapies approved by the FDA.
For the CAR-Ts in development, particularly for indications outside hematology and oncology, the FDA would expect developers to consider new strategies involving targeting insertion of the CAR construct to specific loci, and comprehensive tumor-testing to better characterize the risk and nature of the new cancers caused by the treatment. The CAR-T field of cellular and gene therapy is in a better position than it was 20 years ago in dealing with similar safety events, but that could change if we start seeing a greater number of reports of new cancers in treated patients. That would certainly create a dent in the demand and cost for CAR-T therapies, particularly if the cost includes addressing the long-term risk of these therapies. While the approved CAR-T therapies will potentially deal with these issues with relative ease, for the new therapies in development, the bar just got raised a bit for the FDA approval.
Dr. Mukesh Kumar
Founder & CEO, FDAMap
Linkedin: Mukesh Kumar, PhD, RAC