Personalised cancer medicine: New insights into the benefits and risks of therapies

In multiple myeloma, plasma cells proliferate uncontrollably in the bone marrow, disrupting the growth of healthy blood-forming cells. If the disease recurs after treatment or fails to respond, CAR T-cell therapy may be considered. In this innovative and personalised form of cancer immunotherapy, immune cells (T cells) are taken from the patient and genetically modified in the laboratory to enhance their ability to recognise and attack cancer cells. The modified autologous cells (CAR T cells) are then reinfused into the patient. Once active in the body, they seek out and destroy malignant cells.

A research team led by Leipzig University Medical Center and the Fraunhofer Institute for Cell Therapy and Immunology IZI has examined in greater detail how such living, cell-based therapies act in the body over an extended period. The researchers analysed two CAR T-cell therapies directed against the B-cell maturation antigen (BCMA). BCMA is present on the surface of malignant plasma cells and is therefore a suitable target for therapeutic approaches.

The study involved 61 patients: 34 received CAR T-cell therapy with idecabtagene vicleucel (ide-cel) and 27 were treated with ciltacabtagene autoleucel (cilta-cel). Treatment with cilta-cel led to complete remission in a substantially higher proportion of patients – 78 per cent compared with 38 per cent for ide-cel. It was also associated with longer progression-free survival, meaning that disease control was maintained for a longer period.

Professor Maximilian Merz, who led the study in his role as senior physician and head of the Multiple Myeloma Unit at the University of Leipzig Medical Center, emphasises: “Such insights are highly important for patient care. We were able to show that tumour burden, T-cell fitness and overall systemic inflammation play a major role in determining the success of CAR T-cell therapy.”

The reasons for the improved efficacy and the differing side-effect profiles of the two products are still poorly understood. The project team at the University of Leipzig Medical Center and the Fraunhofer IZI therefore carried out single-cell multi-omics analyses on a total of 135 blood samples. Such investigations make it possible to capture the molecular characteristics of individual cells over an extended period and to track cellular changes in detail. The analyses showed that treatment with cilta-cel induces the expansion of certain immune cells that are important for combating cancer but can also give rise to side effects.

Dr Kristin Reiche, head of the Department of Medical Bioinformatics at the Fraunhofer IZI, explains: “The pharmacokinetics – in other words, how the human body interacts with the two CAR T-cell therapies – differ. Cilta-cel exhibits a delayed onset of expansion but reaches higher cell numbers overall, meaning that CAR T cells proliferate more slowly at first but ultimately more extensively. For this reason, cytokine release syndrome, a possible side effect of the therapy, may also occur later.”