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利用肿瘤浸润淋巴细胞作为载体系统递送至肿瘤的溶瘤腺病毒。

Systemic Delivery of Oncolytic Adenovirus to Tumors Using Tumor-Infiltrating Lymphocytes as Carriers.

机构信息

Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland.

TILT Biotherapeutics Ltd., 00290 Helsinki, Finland.

出版信息

Cells. 2021 Apr 22;10(5):978. doi: 10.3390/cells10050978.

Abstract

Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, studies in hamsters have shown a 100% complete response rate when animals were treated with oncolytic adenovirus coding for TNFa and IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) and TIL therapy. In humans, one caveat with oncolytic virus therapy is that intratumoral injection has been traditionally preferred over systemic administration, for achieving sufficient virus concentrations in tumors, especially when neutralizing antibodies emerge. We have previously shown that 5/3 chimeric oncolytic adenovirus can bind to human lymphocytes for avoidance of neutralization. In this study, we hypothesized that incubation of oncolytic adenovirus (TILT-123) with TILs prior to systemic injection would allow delivery of virus to tumors. This approach would deliver both components in one self-amplifying product. TILs would help deliver TILT-123, whose replication will recruit more TILs and increase their cytotoxicity. In vitro, TILT-123 was seen binding efficiently to lymphocytes, supporting the idea of dual administration. We show in vivo in different models that virus could be delivered to tumors with TILs as carriers.

摘要

肿瘤浸润淋巴细胞 (TIL) 或溶瘤腺病毒的免疫疗法在癌症治疗中显示出很有前景的结果,当作为单独的疗法使用时。当联合使用时,由于溶瘤腺病毒感染和对 T 细胞的免疫刺激作用,抗肿瘤效果协同增强。事实上,在仓鼠中的研究表明,当用编码 TNFa 和 IL-2 的溶瘤腺病毒(Ad5/3-E2F-D24-hTNFa-IRES-hIL2;TILT-123)和 TIL 疗法治疗动物时,动物的完全缓解率达到 100%。在人类中,溶瘤病毒治疗的一个注意事项是,为了在肿瘤中达到足够的病毒浓度,传统上更倾向于瘤内注射而不是全身给药,尤其是当出现中和抗体时。我们之前已经表明,5/3 嵌合溶瘤腺病毒可以与人淋巴细胞结合,以避免中和。在这项研究中,我们假设在全身注射前将溶瘤腺病毒(TILT-123)与 TIL 孵育,将允许病毒递送到肿瘤中。这种方法将在一个自我扩增的产品中同时递送两种成分。TIL 将有助于递送 TILT-123,其复制将招募更多的 TIL 并增加它们的细胞毒性。在体外,TILT-123 被观察到有效地与淋巴细胞结合,支持双重给药的想法。我们在不同的模型中体内显示,TIL 可以作为载体将病毒递送到肿瘤中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23bf/8143525/0b3c71f73848/cells-10-00978-g001.jpg

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