Abstract 2818: Targeting solid tumors with GDT002, a first-in-class γδTCR-based T cell therapy

Abstract

Abstract Broad application of cell therapies like CAR-T have been hampered by a lack of tumor-specific targets. Gadeta leverages the natural HLA-independent tumor recognition capabilities of γδTCRs combined with the proliferative capacity and robust tumor killing of αβT cells to develop tumor-specific cell therapies. γδT cells expressing Vγ9Vδ2 TCRs are the most common subtype found in peripheral blood. They sense the presence of phosphoantigens (pAgs) upregulated in malignant cells due to a dysregulated mevalonate pathway. The Vγ9Vδ2 TCR expressed by GDT002 was isolated from a PBMC-derived γδT cell of a healthy donor and was selected for its broad and strong tumor reactivity. GDT002 is currently being evaluated in a multicenter first-in-human phase 1/2 study for the treatment of Multiple Myeloma (NCT04688853). Here we describe studies carried out to identify potential solid tumor indications which could be effectively targeted by GDT002. Tumor reactivity was tested against cell lines from different cancer types in the presence of pamidronate, a clinically approved N-bisphosphonate that boosts pAgs levels. Significant GDT002 reactivity, in terms of cytotoxicity and cytokine release, was observed against most tumor targets. In a more complex ex vivo 3D co-culture system, GDT002 reactivity was also observed towards a broad panel of patient-derived tumor organoids. In contrast, there was no or very limited GDT002 reactivity against primary healthy cells. From our broad screening of solid tumor types, we identified ovarian cancer as a promising indication for GDT002. GDT002 displayed significant reactivity towards 4/5 ovarian cell lines and 9/10 patient-derived ovarian cancer organoids in the presence of pamidronate. To study GDT002 in vivo, we investigated the biodistribution of i.v. administered pamidronate. In tumor-bearing mice, intra-tumor pamidronate concentrations were detected during the 7-day observation period, allowing targeting by GDT002. Taken together, our results demonstrate that GDT002 has a potent anti-tumor activity across a broad spectrum of solid and liquid tumor types. We have identified ovarian cancer as a potential indication to explore the clinical effect of GDT002 against solid tumors. Citation Format: Esther Drent, Andrea Bisso, Sjoerd Baardman, Dagmar Verweij, Estefania Salcedo, Chris Coomans, Steven Braem, Sander van de Weg, Sara Melief, Haakan Norell, Marleen van Loenen, Stefania Gobessi, Mark Throsby. Targeting solid tumors with GDT002, a first-in-class γδTCR-based T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2818.