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溶瘤呼肠孤病毒增强利妥昔单抗介导的针对慢性淋巴细胞白血病的抗体依赖性细胞毒性作用。

Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia.

作者信息

Parrish C, Scott G B, Migneco G, Scott K J, Steele L P, Ilett E, West E J, Hall K, Selby P J, Buchanan D, Varghese A, Cragg M S, Coffey M, Hillmen P, Melcher A A, Errington-Mais F

机构信息

Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.

St James's University Hospital, Leeds, UK.

出版信息

Leukemia. 2015 Sep;29(9):1799-810. doi: 10.1038/leu.2015.88. Epub 2015 Mar 27.

DOI:10.1038/leu.2015.88
PMID:25814029
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4490165/
Abstract

The naturally occurring oncolytic virus (OV), reovirus, replicates in cancer cells causing direct cytotoxicity, and can activate innate and adaptive immune responses to facilitate tumour clearance. Reovirus is safe, well tolerated and currently in clinical testing for the treatment of multiple myeloma, in combination with dexamethasone/carfilzomib. Activation of natural killer (NK) cells has been observed after systemic delivery of reovirus to cancer patients; however, the ability of OV to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is unexplored. This study elucidates the potential of oncolytic reovirus for the treatment of chronic lymphocytic leukaemia (CLL), both as a direct cytotoxic agent and as an immunomodulator. We demonstrate that reovirus: (i) is directly cytotoxic against CLL, which requires replication-competent virus; (ii) phenotypically and functionally activates patient NK cells via a monocyte-derived interferon-α (IFNα)-dependent mechanism; and (iii) enhances ADCC-mediated killing of CLL in combination with anti-CD20 antibodies. Our data provide strong preclinical evidence to support the use of reovirus in combination with anti-CD20 immunotherapy for the treatment of CLL.

摘要

天然存在的溶瘤病毒（OV）呼肠孤病毒在癌细胞中复制，引起直接细胞毒性，并可激活先天性和适应性免疫反应以促进肿瘤清除。呼肠孤病毒安全，耐受性良好，目前正在与地塞米松/卡非佐米联合用于多发性骨髓瘤治疗的临床试验中。在向癌症患者全身递送呼肠孤病毒后，已观察到自然杀伤（NK）细胞的激活；然而，OV增强NK细胞介导的抗体依赖性细胞毒性（ADCC）的能力尚未得到探索。本研究阐明了溶瘤呼肠孤病毒作为直接细胞毒性剂和免疫调节剂治疗慢性淋巴细胞白血病（CLL）的潜力。我们证明呼肠孤病毒：（i）对CLL具有直接细胞毒性，这需要具有复制能力的病毒；（ii）通过单核细胞衍生的干扰素-α（IFNα）依赖性机制在表型和功能上激活患者NK细胞；（iii）与抗CD20抗体联合增强ADCC介导的CLL杀伤作用。我们的数据提供了强有力的临床前证据，支持将呼肠孤病毒与抗CD20免疫疗法联合用于治疗CLL。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/0952587245f4/leu201588f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/7c77cd797bff/leu201588f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/dad73f47ec73/leu201588f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/3c3594160fa0/leu201588f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/8dd336c8ccb8/leu201588f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/f510f35da96c/leu201588f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/0952587245f4/leu201588f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/7c77cd797bff/leu201588f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/dad73f47ec73/leu201588f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/3c3594160fa0/leu201588f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/8dd336c8ccb8/leu201588f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/f510f35da96c/leu201588f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c55a/4559759/0952587245f4/leu201588f6.jpg

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