510035 Vortragsreihe Medizinische Forschung: "Chancen in der Immuntherapie endokriner Tumoren unter dem Einfluss von Glukokortikoiden auf die Tumorimmunität" (1 UE) (V+Ko) (SoSe 2024)

Immunotherapies have revolutionized the treatment in many tumor entities, while the results in adrenocortical carcinoma (ACC) were rather heterogeneous. ACC is one of the most aggressive endocrine malignancies with poor prognosis and tumor-related glucocorticoid in 60 % of patients that play a major role in T cell depletion.
An improved understanding of the specific resistance mechanisms in ACC and other solid tumors will allow the development of improved immunotherapies.
Therefore, we could prove for the first time the existence of tumor-infiltrating lymphocytes and the expression of the immune checkpoint molecules PD-1, PD-L1, and CTLA-4 that serve as targets for immunotherapies, while considering the impact of glucocorticoid excess.
For the development of novel immunotherapeutic approaches including tumor vaccines and T cell-based treatments, a target identification is essential. Hence, tumor-specific mutant neoantigens that may be recognized by T cells in the context of major histocompatibility complex (MHC) I are promising candidates.
After identification of a tumor-specific antigen (TA), we focused on a new therapeutic approach considering chimeric antigen receptor (CAR)-T cells. Thereby, we demonstrated that our TA is overexpressed in human ACC and the generated TA-targeting CAR-T cells eradicate ACC cells in vitro. However, full efficacy was only seen in CAR-T cells that were desensitized to glucocorticoids by CRISPR/Cas9-mediated genome editing of the glucocorticoid receptor (hGR). These hGRKOTA-CAR-T cells completely eliminated ACC NOD scid gamma xenografts even under hypercortisolemic conditions and succeeded in a complete and sustained remission in 30 % of all mice.
Based on these very promising results, we will further improve this new therapeutic concept to turn an immunologically “cold” tumoral microenvironment that confers to resistance to current immunotherapies into an immunological “hot” solid tumor and expand the scope of additional tumor-specific antigens.

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