In a high-ranking study, researchers from the University Medical Center Leipzig and the Fraunhofer Institute for Cell Therapy and Immunology IZI have investigated the efficacy of two innovative CAR-T cell therapies against the B-cell maturation antigen in patients with difficult-to-treat multiple myeloma. The analysis sheds light on molecular mechanisms that determine the success of these living drugs in blood cancer. Building on this, the team has raised a follow-up project with funding of two million euros to research the next steps in immunotherapy.

Multiple myeloma leads to an uncontrolled proliferation of plasma cells in the bone marrow, which hinders the production of healthy blood cells. In the case of relapses or therapy-resistant cases, CAR-T cell therapy is an option. This personalized cancer immunotherapy takes T cells from the patient’s body and genetically modifies them in the lab so that they can better recognize and fight cancer cells. The altered CAR-T cells are then infused and destroy the malignant cells in the body.

The study focused on two therapies that target B-cell maturation antigen (BCMA), which is expressed on diseased plasma cells. 61 patients were examined: 34 received idecabtagene vicleucel (Ide-Cel), 27 ciltacabtagene autoleucel (Cilta-Cel). Therapy with Cilta-Cel achieved complete remission in 78 percent of those affected, compared to 38 percent for Ide-Cel. It also prolonged progression-free survival, so the disease remained controlled for longer.

The researchers identified factors such as tumor burden, T-cell fitness and systemic inflammation as crucial for therapeutic success. These findings help to select and optimize treatments. To clarify the differences in efficacy and side effects, the scientists performed single-cell multiomics analyses on 135 blood samples. This method records molecular profiles of individual cells over time and tracks changes in detail.

The analyses showed that Cilta-Cel induces an increased expansion of certain immune cells that fight cancer but can also trigger side effects. The pharmacokinetics differ: Cilta-Cel has a delayed but more intensive proliferation of CAR-T cells, which leads to higher cell counts. As a result, cytokine release syndrome, a possible complication, can occur later.

The cooperation between Leipzig University Medical Center and Fraunhofer IZI proved to be successful and led to funding from the Hector Foundation of more than two million euros for a follow-up project. In addition to CAR-T cell therapies, bispecific antibodies have changed the treatment of multiple myeloma in recent years. Three of the four bispecific antibodies approved in Germany also target BCMA. However, these therapies work differently, with varying pharmacokinetic profiles, and are currently used without a fixed sequence.

In the new project, the researchers plan to perform comprehensive multi-omics analyses on samples from patients with relapses to determine how CAR-T cells and bispecific antibodies can be optimally combined or sequenced. The aim is to further improve immunotherapy and develop more personalized approaches that increase treatment success and minimize side effects.

The original study was published in the journal Cancer Cell under the title “A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma”. It provides a detailed atlas of cellular dynamics and identifies predictors of response and toxicity. Such work helps to improve the prognosis for patients with multiple myeloma, a disease that affects thousands of people in Germany every year and is often relapsing.

The University Medical Center Leipzig is one of the leading centers for hematology and oncology in Germany. As part of the Medical Faculty of the University of Leipzig, it integrates clinical care with research and teaching. The Department of Multiple Myeloma, headed by Maximilian Merz, specializes in innovative therapies for plasma cell-based diseases. Fraunhofer IZI in Leipzig focuses on cell therapy and immunology, with expertise in bioinformatics and translational approaches. The Department of Medical Bioinformatics under Kristin Reiche develops methods for the analysis of complex biomedical data.

This cooperation exemplifies the transfer of basic research into the clinic. The integration of single-cell technologies and multi-omics data provides new insights into the immune response in cancer. The funding makes it possible to address open questions, such as the long-term persistence of CAR-T cells or resistance mechanisms. In the long term, this could lead to sequential therapeutic strategies that combine CAR-T with bispecific antibodies to prevent recurrences and prolong survival.

In Germany, CAR-T therapies have been approved for several years, but their use remains limited to specialized centers due to their complexity and cost. The study highlights the need to consider molecular profiles prior to therapy to identify suitable candidates. As the prevalence of multiple myeloma increases due to an aging population, such findings become more relevant. The researchers appeal for closer networking between clinics and research in order to bring innovative immunotherapies into practice more quickly and to increase the quality of life of those affected.

Original Paper:

A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma – ScienceDirect

Editor: X-Press Journalistenbüro GbR

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