Endocrine Abstracts

Glucocorticoids (GC) confer a profound immunosuppressive effect and are extensively used in autoimmune diseases and cancer therapy for their anti-inflammatory properties. However, this mechanism is also exploited by multiple endocrine and non-endocrine cancers that secrete GCs either by active production or metabolite recycling to modulate immune-recognition and –therapy. In this talk, the speaker will provide data on adrenocortical carcinoma (ACC) as perfect exemplary cancer entity to explore the impact of autocrine GC signaling in hormonally active cancers on cancer progression as well as the expression of cancer antigens that can be targeted with CAR-T cell immunotherapy. He will further provide transcriptomic and mechanistic insights in ACC tumor biology, will show how cancer antigens can be modulated to increase CAR-T cell recognition thresholds by GC signaling and demonstrates clinically relevant intratumoral biomarkers for GC secretion and disease progression in ACC. While GC secretion negatively affects conventional CAR-T cell efficacy the presenter will provide further selective T cell engineering capabilities to alleviate the detrimental effects on T cell efficacy on the one hand, while exploiting the exalted GC driven cancer antigen expression on the other. He will provide data that show how GC-resistant CAR-T cells exceed autocrine GC cancer signaling for effective immunotherapeutic targeting while inducing complete and sustained remission in steroidogenic ACC mouse models. Due to the promising curative potency of CAR-T cells in preclinical ACC mouse models, ROR1 CAR-T cells will enter phase I clinical trial at our center, where we will assess safety and tolerability of ACC-directed CAR-T cells in human ACC patients.

Key findings: • Autocrine glucocorticoid (GC) cancer signaling induces cancer progression and antigen expression that can be targeted with genetically modified CAR-T cells.

• ROR1 is an extracellular oncogenic protein that is a suitable CAR-T cell target which further acts as new biomarker for intratumoral glucocorticoid secretion due to its tight regulation by GC signaling.

• Glucocorticoid-resistant CAR-T cells exploit autocrine GC signaling for effective CAR-T cell therapeutic targeting while inducing complete and sustained remission in ACC bearing mice.

ROR1 CAR-T cells will be evaluated in human ACC patients in phase I clinical trial.