癌症研究
T细胞
细胞毒性T细胞
CD8型
免疫疗法
体内
效应器
免疫系统
外周血单个核细胞
离体
抗体
CD3型
体外
生物
免疫学
生物化学
生物技术
作者
Lisa A. King,Elisa C. Toffoli,Myrthe Veth,Victoria Iglesias-Guimarais,Manon C. Slot,Derk Amsen,Rieneke van de Ven,Sarah Derks,Marieke F. Fransen,Jurriaan B. Tuynman,Thilo Riedl,Rob C. Roovers,Anton E.P. Adang,Jurjen M. Ruben,Paul W.H.I. Parren,Tanja D. de Gruijl,Hans J. van der Vliet
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2023-06-27
卷期号:11 (9): 1237-1252
被引量:12
标识
DOI:10.1158/2326-6066.cir-23-0189
摘要
Vγ9Vδ2 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vγ9Vδ2 T cells to EGFR-expressing tumors. An EGFR-Vδ2 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vγ9Vδ2 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vγ9Vδ2 T cells from peripheral blood and tumor specimens of patients with EGFR+ cancers had a distinct immune checkpoint expression profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vγ9Vδ2 T cells could be activated by EGFR-Vδ2 bsTCEs to mediate lysis of various EGFR+ patient-derived tumor samples, and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-Vδ2 bsTCEs exerted preferential activity toward EGFR+ tumor cells and induced downstream activation of CD4+ and CD8+ T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vγ9Vδ2 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-Vδ2 bsTCEs in patients with EGFR+ malignancies.
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