Strijker Josephine G M, Pscheid Ronja, Drent Esther, van der Hoek Jessica J F, Koopmans Bianca, Ober Kimberley, van Hooff Sander R, Kholosy Waleed M, Cornel Annelisa M, Coomans Chris, Bisso Andrea, van Loenen Marleen M, Molenaar Jan J, Wienke Judith
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
Gadeta B.V., 3584 CM Utrecht, The Netherlands.
J Pers Med. 2021 Sep 17;11(9):923. doi: 10.3390/jpm11090923.
Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.
目前，约50%被诊断为高危神经母细胞瘤的患者会因疾病复发或难治而无法存活。实体瘤免疫疗法的最新创新成果前景广阔，但神经母细胞瘤的主要组织相容性复合体I类分子（MHC-I）低表达对T细胞介导的免疫疗法构成了重大挑战。在此，我们提出一种针对神经母细胞瘤的基于T细胞的新型免疫疗法，该方法基于使用TEG002，即经过工程改造以表达特定γδ-T细胞受体的αβ-T细胞，其可独立于MHC-I识别并杀死靶细胞。在共培养杀伤试验中，我们发现，通过γ干扰素（IFNγ）产生量测定，6个神经母细胞瘤类器官中有3个可激活TEG002。转录谱分析表明，这种效应与干扰素信号传导和细胞外基质组织相关过程的活性增加有关。对TEG002随时间对类器官杀伤动态的分析证实，诱导TEG002激活的类器官无论其MHC-I表达如何均被有效杀伤。值得注意的是，TEG002治疗的疗效优于供体匹配的未转导αβ-T细胞或内源性γδ-T细胞。我们的数据表明，TEG002可能是一部分神经母细胞瘤患者有前景的新型治疗选择。
