Project B16
Steroid hormones and cancer immunity – learning from adrenal carcinoma
The interdisciplinary project B16 at the interface of endocrinology and immunotherapy is investigating how the body's own steroid hormones influence the effectiveness of modern cancer immunotherapies. Through close collaboration between the Chair of Endocrinology and Diabetology and the Chair of Cellular Immunotherapy, as well as a strong national and international cooperation network, innovative therapeutic approaches are being developed. The focus is on adrenocortical carcinoma (ACC), a rare, highly aggressive tumour disease with very limited treatment options. Immuno-oncological approaches have so far been only partially effective, which is largely due to the glucocorticoid excess present in about 60% of patients, which suppresses the immune system. Accordingly, ACC tumours show low immune cell infiltration and weak expression of central immune checkpoint molecules.
Against this background, a ROR1-specific CAR-T cell therapy was developed that exhibits strong antitumour activity in preclinical models. However, this is also significantly limited by glucocorticoids. Through targeted CRISPR/Cas9-mediated modification of the glucocorticoid receptor, CAR-T cells were generated that remain resistant to this hormonal inhibition.
These results form the basis for the first clinical study with ROR1-CAR-T cells in ACC (LION-1). Building on this, the current project aims to systematically investigate the influence of other(adrenal) steroid hormones on CAR-T cells. In addition, the safety and efficacy of CAR-T cell therapy in ACC will be further optimised in extended preclinical models with the long-term goal of establishing hormone-resistant immunotherapy.
Specific aims
(I) Investigation of the influence of androgens on the phenotype and functional activity of CAR-T cells in preclinical ACC models in vitro and in vivo
(II) Evaluation of dual antigen targeting and transcription factor engineering to increase the effectiveness and persistence of CAR-T cells and to overcome tumour-associated resistance mechanisms in ACC
(III) Characterisation of the interaction between ROR1-specific CAR-T cells and the endogenous immune system in syngeneic ACC models in immunocompetent mice
| Principal Investigators | Institution |
| Prof. Dr. med. Martin Fassnacht | JMU |
| Dr. rer. nat. Laura-Sophie Landwehr | JMU |
| Prof. Dr. med. Michael Hudecek | JMU |
