Cellular ‘barrier’ discovered in CAR-T-resistant lymphomas
New hope for lymphoma patients as scientists uncover why CAR-T therapy fails, and how to fix it.
A research team from University Hospital Cologne and the University of Cologne’s Faculty of Medicine (both Germany) has uncovered a mechanism that affects the success of CAR-T therapy and could explain why the therapy doesn’t work long-term for approximately half of patients with aggressive B-cell lymphoma.
CAR-T cell therapy has transformed how we treat relapsed or refractory B-cell lymphomas, showing remarkable results and gaining regulatory approval worldwide. However, its long-term success is limited to about half of all patients who receive it. The other 50% either don’t maintain their initial response or experience their cancer returning despite the treatment. Some patients unfortunately die from their disease even after receiving CAR-T therapy.
Scientists don’t fully understand all the reasons behind these treatment failures, which is why more research is critically important. Understanding why CAR-T therapy doesn’t work for everyone could lead to improvements that help more patients achieve lasting remissions.
To gain an understanding of the factors that might be at play, the research team used several advanced laboratory techniques to analyze differences between patients who had long-lasting responses to CAR-T therapy and those whose responses didn’t last.
They employed four methods to examine patient lymphoma samples:
- Bulk RNA sequencing to analyze the overall gene activity in whole samples
- Single-cell RNA sequencing to examine gene activity in individual cells, allowing researchers to identify specific cell types and their behaviors within the tumor environment
- Imaging mass cytometry to create detailed maps of samples showing where different cell types were located and how they interacted with each other
- MACSima imaging cyclic staining to visualize different cellular markers simultaneously, providing comprehensive information about cell types and their relationships
The ultimate goal was to identify specific targets within the tumor microenvironment that could be manipulated to improve CAR-T cell therapy.
CAR-T therapy for T-cell malignancies
An off-the-shelf, CRISPR-edited CAR-T therapy has shown promise for T-cell malignancies, including T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
The team identified CSF1R-positive myeloid-monocytic cells, also called LAMM cells, that were notably increased in patients who don’t respond well to CAR-T therapy. They discovered that LAMM cells suppress CAR-T cells through a specific molecular pathway involving prostaglandin E2 (PGE2) signaling. This interaction occurs between LAMM cells and receptors called EP2 and EP4 on T cells, essentially shutting down the CAR-T cells’ ability to proliferate and kill cancer cells.
“Our results show that these LAMM cells act as a kind of barrier, protecting the tumor from the CAR-T cells. They inhibit the effect of the CAR-T cells, thus preventing the effectiveness of CAR-T cell therapy,” explains Professor Ullrich, who is the last author of the study.
What makes this discovery particularly promising is that the researchers found an existing approved drug, a CSF1R inhibitor, could dismantle this cellular barrier. When combined with CAR-T therapy in preclinical mouse models, treatment effectiveness improved dramatically.
The findings represent a potential breakthrough for patients with limited options and the research team suggest that this therapeutic combination should be tested in clinical studies for patients.
If successful, this approach could transform treatment for thousands of lymphoma patients worldwide who currently face poor prognoses despite cutting-edge immunotherapy.