Abstract LB089: ACE2016: an off-the-shelf EGFR-targeting γδ2 T cell therapy against EGFR-expressing solid tumors

Abstract

Introduction: CAR-αβT therapies have been shown to improve clinical outcomes in hematological malignancies; however, solid tumors still remain as challenges to CAR-αβT therapies due to tumor microenvironment, limited tumor infiltration or antigen escape. Previous research findings indicate γδ2 T cells are involved in tumor surveillance by responding to phosphoantigen overexpressed by most of cancers. The antibody cell conjugation (ACC) technology has the advantage to link cancer-targeting antibodies on cell surface of immune cells without genetic modification. This study applies ACC technology to generate an off-the-shelf EGFR-targeting γδ2 T cell therapy ACE2016, and presents the promising potency of ACE2016 against EGFR-expressing cancer cells. Methods: γδ2 T cells were expanded from healthy donor PBMCs and αβ T cell population were depleted. Both γδ2 T cells and αEGFR were covalently conjugated to selected DNA aptamers that enable DNA hybridization to generate EGFR-targeting γδ2 T cells, ACE2016. The characteristics and antibody conjugation of ACE2016 was evaluated by flow cytometry, and in vitro cytotoxicity and in vivo anti-tumor potency was investigated using luminescence-based cytotoxicity assay and the orthotopical model with EGFR-expressing cancer cells, respectively. Results: ACE2016 showed nearly 100 % of αEGFR antibody conjugation and exhibited EGFR-specific binding activity. These features conferred ACE2016 with enhanced in vitro cytotoxicity against EGFR-expressing cancer cells compared to unconjugated γδ2 T cells, while ACE2016 and γδ2 T cells showed no significant difference of anti-tumor potency against EGFR-negative cancer cells. Further characterization studies demonstrated that co-cultured with target cells significantly activated ACE2016 along with enhanced degranulation and cytokine production without measurable IL-6 secretion. Moreover, ACE2016 suppressed EGFR-expressing breast cancer cells in vivo in the orthotopic xenograft model without weight loss or toxicological observations. Conclusion: ACE2016, an EGFR-targeting γδ2 T cell product, was successfully generated as an effective off-the-shelf treatment for EGFR-expressing solid tumors. This study provides the evidence for the in vitro and in vivo efficacy of ACE2016 against EGFR-expressing cancer cells to support the clinical application against EGFR-expressing tumors. Citation Format: Hao-Kang Li, Tai-Sheng Wu, Pei-Ru Leng, Yi-Chiu Kuo, Zih-Fei Cheng, Chia-Yun Lee, Yan-Liang Lin, Sai-Wen Tang, Shih-Chia Hsiao. ACE2016: an off-the-shelf EGFR-targeting γδ2 T cell therapy against EGFR-expressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB089.

Advancements in γδT cell engineering: paving the way for enhanced cancer immunotherapy

“…This product is currently under phase I trial for patients with relapsed/refractory B-cell lymphomas (NCT05653271). Other products, ACE2016 (EGFR-targeting γδT) and ACE1708 (PD-L1-targeting γδT), are in the preclinical exploratory stage ( 183 ).…”