EYES2023 ESE Young Endocrinologists and Scientists (EYES) 2023 Oral communication 3: Adrenal Tumors and Neuroendocrine Tumors (7 abstracts)
ROR-1 specific CAR-T cells with CRISPR/CAS9 mediated glucocorticoid receptor-knockout exert potent antitumor efficacy in advanced adrenocortical carcinoma
Marc Philipp Schauer 1,2 , Barbara Altieri 1 , Rodrigo A Redondo-Frutos 2 , Peter Spieler 2 , Tanja Maier 3 , Daniel Oppelt 1 , Matthias Kroiss 1,3,4 , Silviu Sbiera 1 , Justus Weber 2# , Martin Fassnacht 1,4# , Laura-Sophie Landwehr 1# & Michael Hudecek 2#
1Department of Internal Medicine I, Division of Endocrinology & Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany; 2Department of Internal Medicine II, Chair for Cellular Immunotherapy, University Hospital, University of Wuerzburg, Wuerzburg, Germany; 3Department of Internal Medicine IV, Division of Endocrinology & Diabetes, LMU Hospital Munich, University of Munich, Munich, Germany; 4Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany.
# These authors contributed equally
Introduction: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with poor prognosis and limited treatment options. In addition, ACC is characterized by endogenous glucocorticoid (GC) excess in 60% of cases which is hypothesized to be one reason, why first clinical trials evaluating the potency of immune checkpoint blockade showed only modest results. Here, we report the identification of ROR-1 as a candidate target for the treatment of ACC and the preclinical assessment of a next-generation CAR-T cell product.
Methods: ROR-1 expression was evaluated in 5 ACC cell lines and 197 ACC tissues. ROR-1 specific CAR-T cells (ROR-1-CART) were generated and functionally tested in preclinical models of ACC.
Results: Our data show ROR-1 transcripts to be detected over background in 92.7% of ACC samples at mRNA (n=62) and in 91.1% at protein level (n=135). ROR-1 expression was 2-fold higher in ACC as compared to normal adrenal glands (P=0.015) and upregulated 3-fold in metastases as compared to primary tumors (P=0.002). ROR-1-CART recognized and potently eradicated ACC tissues in preclinical models. To additionally investigate the potential of GCs on CAR-T cell functions, we desensitized ROR-1-CART by CRISPR/Cas9-mediated genome editing of the hGR locus and found hGRKOROR-1-CART to exert identical antitumor efficacy under normal and immunosuppressive conditions (ROR-1-CART: 41.8% vs hGRKOROR-1-CART: 74.9% specific lysis of NCI-H295R cells, E-T 1:1). Lastly, we compared ROR-1-CART efficacy alone with hGRKO and pharmaceutical blockade of GC effector functions and observed hGRKOROR-1-CART to be superior to a combined treatment approach due to a corticosteroid inhibitor-related downregulation of ROR-1 on ACC tumor cells.
Conclusion: We show that ROR-1 is commonly and homogenously overexpressed in human ACC specimen. Preliminary results also reveal enhanced efficacy of hGRKOROR-1-CART in preclinical models of ACC. Full data will be presented at the meeting.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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