MDC researchers develop strong weapons against lymphomas

MDC researchers have developed a new method for CAR T-cell therapy. The team has shown in Nature Communication that the approach is very effective, especially when it comes to fighting follicular lymphomas and malignant lymphocytic leukemia, the most common type of blood cancer in adults.

The body’s immune system does not usually recognize that cancer cells are dangerous. To correct this sometimes fatal mistake, researchers are exploring a clever new idea, one that involves removing a handful of immune cells from cancer patients and “updating” them. laboratory so that they identify some surface proteins in the malignant cells. The researchers then multiply the immune cells and inject them back into patients’ blood – allowing them to travel through the body to find all the cancer cells and attack them in a targeted way.

In fact, the first treatments based on this idea have already been agreed: So-called CAR T cells have been used in Europe since 2018, especially in patients with B-cell lymphomas for which treatments did not work. normal cancer for them.

T cells are similar to the police force of the immune system. The abbreviation CAR stands for “chimney antigen receptor” – meaning a cellular police force equipped with a new, laboratory-designed special antenna, which targets surface proteins on the cancer cells. Thanks to this antenna, a small number of T cells can surround a large number of cancer cells and destroy them. Ideally, the CAR T cells circulate the body for weeks, months or even years and thus prevent tumor recurrence.

Type of signals for B cells.

Until now, the antenna on the CAR T cells was directed specifically against the CD19 protein, which B cells – a type of immune cell – carry on their surface. However, this type of treatment is not effective in all patients. A team led by Dr. Uta Hoepken, head of Microenvironmental Management at Autoimmunity and Cancer Lab at the Max Delbrueck Center for Molecular Medicine at the Helmholtz Society (MDC), has now developed a new version of this treatment that senses T cells. the laboratory to a different signaling feature: the BX-cell homing protein CXCR5.

“CXCR5 was first described at the MDC over 20 years ago, and I’ve been studying this protein myself for almost as long,” says Hoepken. “So I am very pleased that we have now successfully used CXCR5 to effectively combat non-Hodgkin lymphomas, such as follicular and mantle cell lymphoma as well as malignant lymphocytic leukemias, in the laboratory. . ”This protein is a receptor that helps mature B cells move from bone marrow – where they are excreted – to organs of the immune system such as the lymph nodes and the spleen. “Without the receptor, the B cells would not find their way to their target site, B-cell follicles of those lymphoid organs,” Hoepken explains.

Well-tailored target

“All mature B cells, including malignant ones, carry this receptor on their surface. So we seemed to be well-suited to detect B-cell tumors – like that enables CXCR5 – directed CAR – T cells to attack the cancer, “says Janina Pfeilschifter, a PhD student in Hoepken ‘s team. She and Dr. Mario Bunse from the same research group are the lead authors of the paper, which appeared in the journal Nature Communication. “In our study, we have shown through experiments with human cancer cells and two mouse models that this immunotherapy is more likely to be safe and highly effective,” Pfeilschifter said.

The new approach may be particularly suitable for patients with follicular lymphoma or malignant lymphocytic leukemia (CLL). “Both cancers involve not only B cells but also follicular helper T cells, which also carry CXCR5 on their surface,” Bunse explains. The special antenna for the signaling feature, the CXCR5-CAR, was created by Dr. Julia Bluhm during her time as a PhD student in the MDC Translational Tumorimmunology Lab, called Dr. Armin Rehm over. He and Hoepken are the corresponding authors of the study.

First success in the petri dish

Pfeilschifter and Bunse first showed that different human cells, for example, from blood vessels, the gut and the brain, do not carry the CXCR5 receptor on their surface and so T cells are not equipped with CXCR5-CAR ‘attack them in the petri dish. “This is important to prevent unexpected organ damage during treatment,” Pfeilschifter explains. In contrast, experiments with human tumor cell lines showed that malignant B cells from very different forms of B-non-Hodgkin lymphoma all exhibit their receptors.

Professor Joerg Westermann, from the Department of Hematology, Oncology and Tumor Immunology in the Charite Medical Department – Universitaetsmedizin Berlin at the Virchow Campus Clinic, also donated tumor cells to the team from patients with CLL or B-non-Hodgkin lymphomas. “There, too, we were able to detect CXCR5 on all B-lymphoma cells and follicular helper T cells,” Pfeilschifter says. When she and Bunse combined the tumor cells in the petri dish together with the CAR T cells targeting CXCR5, almost all of the malignant B and T helper cells were removed from the sample. print after 48 hours.

Mice with leukemia were cured

The researchers also tested the new method on two mouse models. “The CAR T cells are inserted into the blood of cancer patients,” Hoepken says. “So animal research is needed to show that the cells are home to the areas where the cancer lives, multiply there and then do the job effectively.”

One model involved animals with a severely suppressed immune system, which could thus be manipulated by human CAR T cells without causing rejection reactions. “We also developed a real mouse model for CLL specifically for the current study,” Bunse reports. “We donated mouse CAR T cells against CXCR5 to these animals by induction and were able to remove mature B cells and T helper cells, including malignant ones, from hair. B-cells of the lymphoid organs. “

The researchers found no side effects in the mice. “We know from experience with cancer patients that CAR T-cell therapy increases the risk of infection for a few months,” Rehm says. But in practice this side effect is almost always manageable.

There is a clinical trial in the works

No laboratory can handle such a study alone. It did not materialize thanks to the successful collaboration between many colleagues at the MDC and Charite. “

Dr. Uta Hoepken, Head of Microenvironmental Management at Autoimmunity and Cancer Lab, Max Delbrueck Center for Molecular Medicine, Helmholtz Society (MDC)

For them, the study is the first step towards creating a “live drug” – similar to other cellular immunotherapies being developed at MDC. “We are already collaborating with two cancer specialists at Charite and are currently working with them to prepare a stage 1/2 clinical trial,” said Rehm, Hoepken’s colleague. Both hope that the first patients will soon benefit from their new CAR-T cell therapy soon.

The German Jose Carreras Foundation for Leukemia has funded the research with around 240,000 euros over three years. The nonprofit group supports advanced research projects and infrastructure projects that study the causes of leukemia and improve treatment, as well as social projects.


Max Delbrück Center for Molecular Medicine at the Helmholtz Society

Magazine Reference:

Bunse, M .., et al. (2021) CXCR5 CAR-T cells simultaneously target non-Hodgkin’s B-cell lymphoma and tumor-supporting follicular helper cells. Nature Communication.