As more patients are surviving for many years thanks to CAR-T cell therapy, long-term side effects are increasingly coming to the fore. Examples include inflammation in the nervous system, prolonged blood count changes and secondary tumors - but above all, infections on a large scale. "This is because the CAR-T cells that remain in the body destroy other immune cells, namely the B cells, which ultimately leads to a lack of antibodies," says Rejeski, "in addition, persistent cytopenias and long-term reduced endogenous T cells, for example due to the initial lymphodepletion, can weaken the immune system in the long term."

"That's why," continues the physician and research group leader, "infections should not be trivialized, because they can occur frequently and can also be serious, and we need to keep that in mind." In order to systematically identify and treat them in the best possible way, research is needed at university hospitals. And research at university hospitals requires structured data collection, also in close cooperation with the doctors in private practice who care for the patients in the long term.

With this in mind, "we need new reporting systems with defined standards for CAR-T associated infections," says Rejeski. Standards that answer questions such as: When did the infection occur - in the first 30 days or after? Was it a bacterial or viral infection or a fungal infection? How serious was it? Did it occur when the patient was in hospital or when the patient was at home? Did the patient have antibiotic prophylaxis while developing this infection?

"This is all information we need to be able to compare the risk of infection between different CAR-T products according to the same standards. "Here," Rejeski continues, "we urgently need to improve."

IAGO should also help with this. IAGO stands for "Identification - Attribution - Grading - Optimization". This strategy is intended to address each new group of side effects in a structured manner, including infections as well as, for example, new neurological side effects that have recently emerged or the development of tumors that may be related to CAR-T treatment.

The first step involves identifying and describing side effects according to their frequency, severity and consistency. The second, "attribution", is about whether side effects that occur are really causally attributable to the treatment. The third step, the establishment of a grading system, revolves around the clinical evaluation of side effects according to a standardized system. Once established, it should be used by all practitioners.

And finally: "optimization", i.e. optimizing the management of the described side effect using new therapeutic approaches. "All of this," says Rejeski, "is the framework for mastering the villain of side effects." And a central task for the doctors and researchers who will be using CAR-T cell therapy in the coming years.

Rejeski, K., Hill, J.A., Dahiya, S. et al. Noncanonical and mortality-defining toxicities of CAR T cell therapy. Nat Med (2025). DOI: https://doi.org/10.1038/s41591-025-03813-5