ACC Immunotherapy with glucocorticoid-resistant CAR-T-cells plus CAR-macrophages
Michael Hudecek · Martin Fassnacht · Pierre Val (University Hospital of Würzburg · Université Clermont Auvergne)
Disease information: Adrenocortical carcinoma (ACC) is a cancer of the adrenal gland and difficult to treat with currently available strategies that include surgery to remove the tumor, chemotherapy to eliminate tumor cells and antibodies that activate the immune system. Unfortunately, in most patients with ACC, these treatment strategies only have a short-term effect (and provide benefit for several months) and cannot prevent the tumor from recurring and spreading in the body. Therefore, many patients face a severe prognosis with a mean survival of only few years from diagnosis, similar to other difficult-to-treat cancers like pancreatic cancer. Therefore, cancer researchers and clinicians are working relentlessly to develop novel therapies for ACC that are more effective but also well tolerable, safe and accessible.
Background of the research project: This project is taking an entirely new approach to tackle ACC with an immune cell therapy called CAR-T cell therapy (CAR = chimeric antigen receptor). CAR-T cells therapy is an approved, highly effective therapy to treat certain types of leukemia, where it is used as an one-off treatment with a single infusion that requires only a short hospital stay. This therapy is a new class of cellular immunotherapy where a patient’s immune cells are redirected by genetic engineering to seek and destroy ACC tumor cells in the body. A key advantage is that CAR-T cells can destroy ACC tumor cells in the adrenal gland and distant tumor sites (metastases), do not cause the side effects of chemotherapy, and can form memory CAR-T cells that prevent tumor relapse. However, intensive research will be necessary to fine tune the CAR-T cell approach and achieve this ideal outcome in ACC. In their recent work, the project leaders have identified a molecule called ROR1 that is present on ACC tumor cells and now target with CAR-T cells in the first clinical trial with CAR-T cells in ACC worldwide (LION-1 trial) that just began in began in May 2025.
Key objectives of the research project: Building on the foundation of the LION-1 trial and the work with CAR-T cells targeting the ROR1 molecule on ACC, we will take three critical measures to augment and fine-tune this approach and exploit the full potential of this immune cell therapy. First, we will engage our CAR-T cells in an immune cell team action with macrophages (“big eater cells”) to make sure that all ACC tumor cells are eliminated and do not escape from our treatment. To foster the team action, we will instruct CAR-T cells to release molecules that are called cytokines that help them to communicate with macrophages, and will also equip macrophages with a CAR. Second, we shield CAR-T cells and CAR-macrophages from factors that the ACC tumor uses to neutralize the immune system, such as the release of steroid hormones. Third, we will use laboratory models and go through several optimization cycles to determine the optimal blend of CAR-T cells plus CAR-macrophages (high efficacy, high safety) and then integrate the optimal approach into our clinical trial.
Expected results, knowledge utilisation and impact on health care: We expect that CAR-T cells and CAR-macrophages will cooperate and work highly synergistically against ACC. This will allow us to increase short- and long-term efficacy, but also safety when a smaller dose of immune cells can be administered. This knowledge will directly feed into our LION-1 clinical trial and can be extrapolated to other types of cancer. The CAR-T plus CAR-marophage therapy is designed as a one-off single infusion treatment, that can ultimately be delivered in an outpatient setting, with a highly positive impact in patient quality of life, and reducing the burden on patients and health care providers.