携带药物的工程化 γδ T 细胞在骨肉瘤的临床前模型中显示出增强的细胞毒性、持久性和疗效。

Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma.

机构信息

UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.

UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, WC1E 6DD London, UK.

出版信息

Sci Transl Med. 2024 May 29;16(749):eadg9814. doi: 10.1126/scitranslmed.adg9814.

Abstract

T cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβ T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent cellular cytotoxicity, and minimal alloreactivity. We present an immunotherapeutic platform technology built around the innate properties of the Vγ9Vδ2 T cell, harnessing specific characteristics of this cell type and offering an allocompatible cellular therapy that recruits bystander immunity. We engineered γδ T cells to secrete synthetic tumor-targeting opsonins in the form of an scFv-Fc fusion protein and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15). Using GD2 as a model antigen, we show that GD2-specific opsonin-secreting Vγ9Vδ2 T cells (stIL15-OPS-γδ T cells) have enhanced cytotoxicity and promote bystander activity of other lymphoid and myeloid cells. Secretion of stIL-15 abrogated the need for exogenous cytokine supplementation and further mediated activation of bystander natural killer cells. Compared with unmodified γδ T cells, stIL15-OPS-γδ T cells exhibited superior in vivo control of subcutaneous tumors and persistence in the blood. Moreover, stIL15-OPS-γδ T cells were efficacious against patient-derived osteosarcomas in animal models and in vitro, where efficacy could be boosted with the addition of zoledronic acid. Together, the data identify stIL15-OPS-γδ T cells as a candidate allogeneic cell therapy platform combining direct cytolysis with bystander activation to promote tumor control.

摘要

基于 T 细胞的癌症免疫疗法通常依赖于嵌合抗原受体等膜结合细胞毒性增强剂,这些受体表达在自体αβ T 细胞中。这些方法受到合成构建体的持续信号和与制造相关的成本的限制。γδ T 细胞是细胞治疗的一种新兴替代方法,具有先天的抗肿瘤活性、强大的抗体依赖性细胞细胞毒性和最小的同种异体反应性。我们提出了一个围绕 Vγ9Vδ2 T 细胞的先天特性构建的免疫治疗平台技术,利用这种细胞类型的特定特征,并提供一种同种异体兼容的细胞疗法,招募旁观者免疫。我们设计了 γδ T 细胞以 scFv-Fc 融合蛋白和有丝分裂原 IL-15Rα-IL-15 融合蛋白(stIL15)的形式分泌合成的肿瘤靶向调理素。使用 GD2 作为模型抗原,我们表明 GD2 特异性调理素分泌 Vγ9Vδ2 T 细胞(stIL15-OPS-γδ T 细胞)具有增强的细胞毒性,并促进其他淋巴样和髓样细胞的旁观者活性。stIL-15 的分泌消除了对外源细胞因子补充的需求,并进一步介导了旁观者自然杀伤细胞的激活。与未经修饰的 γδ T 细胞相比,stIL15-OPS-γδ T 细胞在体内对皮下肿瘤的控制和在血液中的持久性更好。此外,stIL15-OPS-γδ T 细胞在动物模型和体外对患者来源的骨肉瘤有效,并且可以通过添加唑来膦酸来提高疗效。总之,这些数据表明 stIL15-OPS-γδ T 细胞是一种同种异体细胞治疗平台的候选物,该平台将直接细胞溶解与旁观者激活相结合,以促进肿瘤控制。

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