Oncolytic adenovirus MEM-288 encoding membrane-stable CD40L and IFNβ induces an anti-tumor immune response in high grade serous ovarian cancer

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology Neoplasia Pub Date : 2024-09-13 DOI:10.1016/j.neo.2024.101056

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Abstract

Single agent immune checkpoint inhibitors have been ineffective for patients with advanced stage and recurrent high grade serous ovarian cancer (HGSOC). Using pre-clinical models of HGSOC, we evaluated the anti-tumor and immune stimulatory effects of an oncolytic adenovirus, MEM-288. This conditionally replicative virus encodes a modified membrane stable CD40L and IFNβ. We demonstrated this virus successfully infects HGSOC cell lines and primary human ascites samples in vitro. We evaluated the anti-tumor and immunostimulatory activity in vivo in immune competent mouse models. Intraperitoneal delivery of MEM-288 decreased ascites and solid tumor burden compared to controls, and treatment generated a systemic anti-tumor immune response. The tumor microenvironment had a higher proportion of anti-tumor macrophages and decreased markers of angiogenesis. MEM-288 is a promising immunotherapy agent in HGSOC, with further pre-clinical studies required to understand the mechanism of action in the peritoneal microenvironment and clinical activity in combination with other therapies.

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编码膜稳定 CD40L 和 IFNβ 的溶瘤腺病毒 MEM-288 在高级别浆液性卵巢癌中诱导抗肿瘤免疫反应

单药免疫检查点抑制剂对晚期和复发性高级别浆液性卵巢癌（HGSOC）患者无效。我们利用 HGSOC 临床前模型，评估了溶瘤腺病毒 MEM-288 的抗肿瘤和免疫刺激作用。这种有条件复制的病毒编码一种改良的膜稳定 CD40L 和 IFNβ。我们证明了这种病毒能在体外成功感染 HGSOC 细胞系和原发性人类腹水样本。我们在免疫功能正常的小鼠模型中评估了该病毒在体内的抗肿瘤和免疫刺激活性。与对照组相比，腹腔注射 MEM-288 可减少腹水和实体瘤的负担，并且治疗可产生全身性的抗肿瘤免疫反应。肿瘤微环境中的抗肿瘤巨噬细胞比例更高，血管生成标志物减少。MEM-288是一种很有前景的HGSOC免疫疗法药物，还需要进一步的临床前研究来了解其在腹膜微环境中的作用机制以及与其他疗法联合使用的临床活性。

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.