Federica Galvagno, Valeria Leuci, Annamaria Massa, Chiara Donini, Ramona Rotolo, Sonia Capellero, Alessia Proment, Letizia Vitali, Andrea Maria Lombardi, Valentina Tuninetti, Lorenzo D'Ambrosio, Alessandra Merlini, Elisa Vigna, Giorgio Valabrega, Luca Primo, Alberto Puliafito, Dario Sangiolo
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Here, we explored the activity of cytokine-induced killer lymphocytes (CIK), redirected by CAR against mesothelin (MSLN-CAR.CIK), within reductionistic 3D models resembling the structural complexity of both liquid and solid components of PC. MSLN-CAR.CIK effectively killed and were functionally efficient against OC targets. In a \"floating-like\" 3D context with floating OC spheroids, both tumor localization and killing by MSLN-CAR.CIK were significantly boosted by fluid flow. In a \"solid-like\" context, MSLN-CAR.CIK were recruited through the extracellular matrix on embedded tumor aggregates, with variable kinetics depending on the effector-target distance. Furthermore, MSLN-CAR.CIK penetrated the inner levels of OC spheroids exerting effective tumor killing. 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引用次数: 0
摘要
使用 CAR 重定向淋巴细胞的腹膜内细胞免疫疗法是一种针对卵巢癌腹膜癌肿(PC)的有趣方法,目前正在进行临床试验评估。卵巢癌腹膜癌肿显示出一种复合结构,即腹水中漂浮的肿瘤细胞和侵入腹膜的实性肿块。因此,一个全面的实验模型对于在这种特殊环境中优化 CAR 细胞疗法至关重要。在这里,我们探索了细胞因子诱导的杀伤性淋巴细胞(CIK)的活性,CAR 针对间皮素(MSLN-CAR.CIK)重定向的杀伤性淋巴细胞在还原三维模型中的活性,该模型类似于 PC 的液体和固体成分的复杂结构。MSLN-CAR.CIK能有效杀死OC靶标,并具有高效的功能。在浮动 OC 球体的 "浮动类 "三维环境中,流体流动显著促进了 MSLN-CAR.CIK 的肿瘤定位和杀伤作用。在 "类固体 "环境中,MSLN-CAR.CIK通过细胞外基质被吸引到嵌入的肿瘤聚集体上,其动力学变化取决于效应物与靶标的距离。此外,MSLN-CAR.CIK 还能穿透 OC 球体内部,有效杀死肿瘤。我们的研究结果为腹腔内使用 CAR.CIK 的治疗方法提供了目前未知的相关信息,支持了针对 OC PC 患者的局部区域细胞治疗方法临床研究的进一步发展和改进。
Three-dimensional dynamics of mesothelin-targeted CAR.CIK lymphocytes against ovarian cancer peritoneal carcinomatosis.
Intraperitoneal cellular immunotherapy with CAR-redirected lymphocytes is an intriguing approach to target peritoneal carcinomatosis (PC) from ovarian cancer (OC), which is currently evaluated in clinical trials. PC displays a composite structure with floating tumor cells within ascites and solid-like masses invading the peritoneum. Therefore, a comprehensive experimental model is crucial to optimize CAR-cell therapies in such a peculiar environment. Here, we explored the activity of cytokine-induced killer lymphocytes (CIK), redirected by CAR against mesothelin (MSLN-CAR.CIK), within reductionistic 3D models resembling the structural complexity of both liquid and solid components of PC. MSLN-CAR.CIK effectively killed and were functionally efficient against OC targets. In a "floating-like" 3D context with floating OC spheroids, both tumor localization and killing by MSLN-CAR.CIK were significantly boosted by fluid flow. In a "solid-like" context, MSLN-CAR.CIK were recruited through the extracellular matrix on embedded tumor aggregates, with variable kinetics depending on the effector-target distance. Furthermore, MSLN-CAR.CIK penetrated the inner levels of OC spheroids exerting effective tumor killing. Our findings provide currently unknown therapeutically relevant information on intraperitoneal approaches with CAR.CIK, supporting further developments and improvements for clinical studies in the context of locoregional cell therapy approaches for patients with PC from OC.
期刊介绍:
Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions.
The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.