New resistance mechanism discovered in CAR-T cell therapy

A research team from University Hospital Cologne and the University of Cologne’s Faculty of Medicine, led by Professor Dr Dr Roland Ullrich, Senior Physician at the Clinic I of Internal Medicine, has discovered a previously unknown mechanism that could explain why many patients with aggressive B-cell lymphoma do not respond to CAR-T cell therapy in the long term. The results of the study suggest that combining this innovative treatment with other therapies could further improve its effectiveness. The results have been published in the journal Cancer Cell.
In recent years, CAR-T cell therapy has revolutionized the treatment of patients with so-called ‘relapsed or refractory (r/r)’ aggressive B-cell lymphomas – i.e. lymphoma defined by disease relapse or a therapy-resistant course. This process involves the genetic modification of patient’s own T cells so that they can specifically recognize and destroy the cancer cells. CAR-T cells targeting the B-cell marker CD19 have proven to be highly effective and have been approved worldwide for treating patients suffering from aggressive B-cell lymphomas. However, this therapy is effective for around half of patients in the long term. Approximately 50 per cent of patients treated with CAR-T cells do not show a durable response and experience a relapse or die from their disease despite treatment. There are many reasons for this, and more research in this field is urgently needed.
In order to investigate these unanswered questions, the Cologne research team, which includes the first authors of the paper, Dr David Stahl, Dr Philipp Gödel and Dr Hyatt Balk-Want, analysed patient samples before and after CAR-T cell treatment using state-of-the-art cell biology methods. The researchers discovered a specific type of immune cells, so-called CSF1R-positive myeloid-monocytic cells (also known as LAMM cells), which were notably increased in patients without a durable response. They demonstrated that these LAMM cells specifically impair the therapeutic function of the CAR-T cells against the lymphoma and are therefore contributing to the failure of CAR-T cell therapy.
“Our results show that these LAMM cells act as a kind of barrier, protecting the tumour 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.
Strikingly, the authors could demonstrate in the preclinical mouse model that the effectiveness of CAR-T cells is significantly improved if the LAMM cells are targeted using an already approved drug, a CSF1R inhibitor. These findings are an important step towards a new combination therapy involving the use of CAR-T cells together with a CSF1R inhibitor. 
The project is funded by the Collaborative Research Centre 1530 - Elucidation and targeting of pathogenic mechanisms in B cell malignancies, which aims to develop new targeted therapeutic approaches by discovering new pathomechanisms and thus improve the cure rate of patients diagnosed with B-cell neoplasias with a negative prognosis. The next step is to test this approach in a clinical trial with patients suffering from aggressive B-cell lymphoma.