A double-pronged attack on malignant B cells

Multiple myeloma, a cancer of the bone marrow, remains difficult to treat despite modern CAR T cell therapies. In “Molecular Therapy,” a team led by Armin Rehm presents an improved immunotherapy that recognizes two distinct features of malignant cells to destroy the cancer more effectively.

Multiple myeloma is a devastating diagnosis. The disease usually develops in the bone marrow where mature B cells called plasma cells begin to proliferate uncontrollably and produce excessive amounts of antibodies, some of which are defective. The cancer, which destroys bone and other tissues, can become extremely painful. To date, it remains uncurable.

In recent years, modern CAR T cell therapies have significantly extended the lives of many myeloma patients, but their effectiveness has been limited. “In some patients, the treatment does not work at all. In others, relapse occurs sooner or later, which then often rapidly leads to death,” explains Dr. Armin Rehm, Group Leader of the Translational Tumorimmunology lab at the Max Delbrück Center.

In the journal “Molecular Therapy,” the Berlin-based researcher, Dr. Uta Elisabeth Höpken, also at the Max Delbrück Center, and an international team present an optimized immunotherapy: CAR T cells that bind to two receptors simultaneously to destroy cancer cells instead of just one, as was previously the case.

Not all patients express the BCMA receptor

Before the advent of CAR T cell therapy, multiple myeloma was treated with chemotherapy and antibody-based drugs, and sometimes combined with autologous stem cell transplants. These approaches, however, were not curative either. CAR T-cell therapies gave patients new hope.

The treatment involves collecting T cells from patients and genetically engineering them in a bioreactor to express a chimeric antigen receptor, or CAR. These receptors act as sensors that help immune cells detect specific surface proteins. In the case of multiple myeloma, the target is BCMA, a protein found almost exclusively on plasma cells, and not on normal B cells. The modified T cells are then reinfused into patients, where they seek out and destroy cancer cells in the body.

“However, BCMA protein isn’t present on all malignant plasma cells,” says Rehm. In some patients with multiple myeloma, it’s not detectable at all; in others, it disappears over the course of treatment. “That’s why we combined three methods – single-cell RNA sequencing, immunohistochemistry, and flow cytometry – to search for another surface marker characteristic of malignant B cells. That led us to BAFF-R,” says Dr. Agnese Fiori, the study’s first author and a member of Rehm’s team, who now conducts research at Charité- Universitätsmedizin Berlin.

Prevention and treatment of relapse

Two additional researchers also made significant contributions to the study: Professor Jörg Westermann, Deputy Clinic Director and Head of Hematological Diagnostics at Charité, and Professor Jan Krönke, Head of the Department of Internal Medicine C – Hematology, Oncology, Stem Cell Transplantation, and Palliative Medicine at Greifswald University Medical School.

“BAFF-R is particularly abundant on cells from multiple myeloma patients who have relapsed,” says Fiori. In addition, it is often found on abnormal plasma cells without BCMA, which are resistant to conventional treatments. “Therapeutically, it therefore makes sense in two respects to use CAR-T cells that recognize both BCMA and BAFF-R,” explains Rehm.

Around 5 to 30 percent of all patients with multiple myeloma could benefit from this dual approach, adds Rehm. For personalized therapy, it is crucial to identify these patients using an appropriate test before treatment begins, he explains. Such screening would be easy to implement in clinical practice.

Success in experiments with cancer cells

Rehm and his colleagues have tested the bispecific CAR T cells both in multiple myeloma cell lines and in patient-derived bone marrow cells. “In all of our experiments, we showed that the improved CAR T cells remain effective, even when the BCMA receptor is absent or has been lost due to therapy – that is, even when treatment with monospecific CAR T cells has failed,” he explains. He hopes that the new approach can prevent relapse in many patients and also extend lifespan – perhaps even offer a cure.

“To truly assess the potential of our method, an initial clinical trial is now necessary,” Rehm adds. Together with colleagues from the National Center for Tumor Diseases (NCT) –  a long-term collaboration between the German Cancer Research Center (DKFZ), excellent partners in university medicine, and other outstanding research partners at various locations in Germany, including the Max Delbrück Center, Charité, and the Berlin Institute of Health (BIH) as partner sites in Berlin – he plans to apply for the requisite funding.  He hopes patients may soon be able to benefit from the optimized CAR T cells.