Abstract LB-104: Targeting solid malignancies with TEGs: αβT cells engineered to express a defined γδTCR in xenograft mice model

Abstract

Abstract γδT cells mediate cancer immune surveillance by sensing metabolic changes of malignant cells via their γδT cell receptor (TCR). Activation of γδTCR is independent of MHC molecules, making them a valuable addition to current treatment strategies. Moreover, γδTCR are able to differentiate between healthy and leukemic stem cells. This concept led to the development of next generation CAR T cells, so-called TEGs: αβT cells Engineered to express a defined γδTCR. A particular γ9δ2TCR, isolated from “clone 5”, has been selected as the candidate for clinical testing (TEG001). A purification strategy was introduced that combined maximal interference of γδTCR chains with endogenous TCR chains with a GMP-grade anti-αβTCR-bead-based depletion strategy to obtain a pure population of engineered immune cells (Straetemans et al. 2015). TEG001 cells showed a strong and broad recognition of hematological malignancies against both cell lines and primary AML (Marcu-Malina et al. 2011, Gründer et al. 2012). To further broaden the clinical implementation of this novel strategy we here investigated the in vivo efficacy profile against solid malignancies. In this study, we evaluated clinical potency of TEG001 against human organoids engineered with most frequent mutations for colorectal cancer, including APC knockout (APCKO), constitutively active KRAS (KRASG12D), P53 knockout (P53KO), and SMAD4 knockout (SMAD4KO), also known as quadruple mutant organoids. These organoids are tumorigenic and can be successfully engrafted as solid tumor mass in immunodeficient mice (Fumagalli et al., 2017; Drost et al., 2015). Irradiated NSG mice received luciferase-positive quadruple mutant organoids subcutaneously and were subsequently infused with TEGs. Tumor growth was measured by bioluminescence imaging. TEG001 showed reduced tumor growth of quadruple mutant organoids compared to untreated and mock controls. Moreover, TEG001-treated mice showed increased overall survival relative to the control mice, followed up to 130 days after treatment. Our current data shows that TEG001 mediates antitumor reactivity against quadruple mutant organoids as solid tumor model in vivo. This xenograft model allows further preclinical testing of next generation TEGs targeted to solid malignancies. Importantly, TEGs are a promising addition to the currently available immune therapeutic strategies as they target cancer as a metabolic disorder. Citation Format: Inez Johanna, Trudy Straetemans, Sabine Heijhuurs, Koen Jansen, Jacco van Rheenen, Jarno Drost, Zsolt Sebestyen, Jurgen Kuball. Targeting solid malignancies with TEGs: αβT cells engineered to express a defined γδTCR in xenograft mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-104.