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KS01.7.A ADAPTOR FITC CAR T-CELLS AND OCTO-FLUO ELICIT PROMISING ANTITUMOR ACTIVITY IN MENINGIOMA VIA SSTR2

2023; Oxford University Press; Volume: 25; Issue: Supplement_2 Linguagem: Inglês

10.1093/neuonc/noad137.009

1523-5866

Jun Chen, C. Pellegrino, Max Mastall, Luis Padevit, Nicholas Favalli, Gabriele Bassi, M Neidert, Flavio Vasella, Patrick Roth, D Neri, Markus G. Manz, Michael Weller, Hans‐Georg Wirsching,

CAR-T cell therapy research

Abstract BACKGROUND Effective treatment options for meningioma patients beyond surgical resection and radiotherapy are lacking. Somatostatin receptor (SSTR) 2 is expressed by most meningiomas. Here, we report pre-clinical and translational evidence for the activity of an SSTR2-targeted adaptor CAR T cell system in meningiomas. MATERIAL AND METHODS Tissue microarrays of meningioma (N=384) patient samples stained for SSTR2. Fluorescein-linked, octameric cyclic peptide SSTR2 antagonist OCTO-FLUO (kindly provided by Philogen, Otelfingen, Switzerland). Adaptor FITC CAR T-cells generated by lentiviral transduction of healthy donor T-cells. Flow cytometry-based killing assays in vitro in SSTR2-expressing meningioma (Ben-Men-1 IOMM-Lee) cells, and ex vivo utilizing freshly dissociated surgical meningioma specimens, by co-incubation with OCTO-FLUO and adaptor FITC CAR T-cells. Orthotopic growth and mouse survival following subdural implantation of IOMM-Lee cells, genetically engineered to express luciferase, i.v. treated with OCTO-FLUO and intratumoral injection of CAR T-cells. RESULTS SSTR2 expression was overall heterogeneous and was high or intermediate in most World Health Organization (WHO) grade 2 (87.8 %) or grade 3 (87.5 %) meningiomas. In vitro, 10 nM was determined as the optimal concentration of OCTO-FLUO, yielding tumor cell killing within 72 hours at effector-target cell (ET) ratios as low as 1:100 in Ben-Men-1 (CAR vs untransduced T-cells [UTT] 47.9 % vs 4.7 %, p < 0.001) and IOMM-Lee (CAR vs UTT 40.2 % vs 4.9 %, p < 0.001) cells. Tumor growth inhibition by the adaptor FITC CAR T-cell system in vivo was confined to SSTR2 expressing cells and was paralleled by prolonged survival compared to UTT in IOMM-Lee (hazard ratio [95% confidence interval], 0.3 [0.1 - 0.9], p=0.030). Preliminary ex vivo killing assays employing freshly dissociated patient samples yielded specific lysis-rates in the range of 15-20% (ET 1:1) at 12 hours. Updated ex vivo results employing optimized protocols will be presented at the conference. CONCLUSION Targeting SSTR2 positive meningioma cells with an adaptor FITC CAR T-cell system is feasible. Syngeneic murine models and the use of adaptor molecules directed against murine SSTR2 will be required to explore secondary immune reactions and off-tumor effects prior to proceeding to early phase clinical trials.