Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology Pub Date : 2024-05-23 DOI:10.1002/cti2.1512

Veronika Bandara, Victoria M Niktaras, Vasiliki J Willett, Hayley Chapman, Noor A Lokman, Anne M Macpherson, Silvana Napoli, Batjargal Gundsambuu, Jade Foeng, Timothy J Sadlon, Justin Coombs, Shaun R McColl, Simon C Barry, Martin K Oehler, Carmela Ricciardelli

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Abstract

Objectives

Recent studies have identified expression of the non-functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour-associated antigen candidate for chimeric antigen receptor (CAR)-T-cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7-CAR-T cells on ovarian cancer using in vitro and in vivo models.

Methods

We evaluated the effects of nfP2X7-CAR-T cells on ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9) and primary serous ovarian cancer cells derived from patient ascites in vitro using monolayer and 3D spheroid assays. We also evaluated the effects of nfP2X7-CAR-T cells on patient-derived tissue explants, which recapitulate an intact tumour microenvironment. In addition, we investigated the effect of nfP2X7-CAR-T cells in vivo using the OVCAR-3 xenograft model in NOD-scid IL2Rγnull (NSG) mice.

Results

Our study found that nfP2X7-CAR-T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un-transduced CD3⁺ T cells in vitro. However, no significant effects of nfP2X7-CAR-T cells were observed for SKOV3 or normal peritoneal cells (LP-9) cells with low P2X7 receptor expression. Treatment with nfP2X7-CAR-T cells increased apoptosis compared with un-transduced T cells in patient-derived explants and correlated with CD3 positivity. Treatment with nfP2X7-CAR-T cells significantly reduced OVCAR3 tumour burden in mice compared with un-transduced CD3 cells for 7–8 weeks.

Conclusion

This study demonstrates that nfP2X7-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.

Abstract Image

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靶向无功能 P2X 嘌呤受体 7 (P2X7) 受体的工程 CAR-T 细胞作为卵巢癌的新型疗法

目的最近的研究发现，包括卵巢癌在内的多种恶性细胞上都表达了无功能 P2X7（nfP2X7）受体，但正常细胞上却没有表达，这使其成为嵌合抗原受体（CAR）-T 细胞免疫疗法的一个有希望的肿瘤相关抗原候选者。在本研究中，我们利用体外和体内模型评估了 nfP2X7-CAR-T 细胞对卵巢癌的细胞毒性作用。方法我们使用单层和三维球状实验评估了 nfP2X7-CAR-T 细胞对卵巢癌细胞系（SKOV-3、OVCAR3、OVCAR5）、正常腹膜细胞（LP-9）和从患者腹水中提取的原发性浆液性卵巢癌细胞的体外效应。我们还评估了 nfP2X7-CAR-T 细胞对患者组织外植体的影响，这些外植体再现了完整的肿瘤微环境。此外，我们还利用 NOD-scid IL2Rγnull (NSG) 小鼠的 OVCAR-3 异种移植模型研究了 nfP2X7-CAR-T 细胞在体内的作用。结果我们的研究发现，与体外未转导的 CD3+ T 细胞相比，nfP2X7-CAR-T 细胞具有细胞毒性，能显著抑制 OVCAR3、OVCAR5 和原发性浆液性卵巢癌细胞的存活。然而，nfP2X7-CAR-T 细胞对 P2X7 受体表达较低的 SKOV3 细胞或正常腹膜细胞（LP-9）没有明显作用。与未转导的T细胞相比，用nfP2X7-CAR-T细胞处理患者衍生外植体会增加细胞凋亡，并与CD3阳性相关。与未转导的 CD3 细胞相比，使用 nfP2X7-CAR-T 细胞治疗小鼠 7-8 周，可显著减少小鼠的 OVCAR3 肿瘤负荷。结论本研究表明，nfP2X7-CAR-T 细胞作为一种新型卵巢癌免疫疗法具有巨大的开发潜力。

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来源期刊

Clinical & Translational Immunology Medicine-Immunology and Allergy

CiteScore

12.00

自引率

1.70%

发文量

审稿时长

13 weeks

期刊介绍： Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.