溶瘤病毒联合免疫治疗在恶性肿瘤治疗中的应用进展

doi:10.19401/j.cnki.1007-3639.2024.07.008

摘要/Abstract

摘要：

溶瘤病毒（oncolytic virus，OV）疗法通过溶瘤病毒在感染的肿瘤细胞内复制、裂解杀死肿瘤细胞，并促进“冷”-“热”肿瘤转换重塑肿瘤免疫微环境，诱导机体免疫系统对肿瘤细胞展开攻击从而达到抗肿瘤治疗的目的。病毒种类、病毒自身特征、宿主免疫力、给药途径及瘤种选择是OV高效发挥抗肿瘤作用的关键。随着基因工程技术的发展，OV可以经过基因编辑改造提高其针对肿瘤细胞的靶向性，增强其复制和裂解细胞的潜能并增强宿主抗肿瘤免疫水平，同时通过联合其他治疗方式可以增强抗肿瘤疗效。肿瘤的异质性是提升肿瘤治疗效果需要突破的瓶颈。鉴于目前临床上单一应用OV疗法的疗效有限，而OV疗法与免疫治疗在抗肿瘤作用机制上存在互补，其联合应用可能为肿瘤治疗提供新的策略。本文从临床获批的OV以及处于研究阶段的天然的或经基因编辑的OV种类、特点及抗肿瘤机制方面展开，同时对处于临床试验阶段的OV治疗进行梳理，总结OV联合治疗策略，尤其是联合以免疫检查点抑制剂（immune checkpoint inhibitor，ICI）和过继细胞疗法（adoptive cell therapy，ACT）为代表的肿瘤免疫治疗进行深入阐述，结合本项目组在OV研究中积累的经验提出OV在抗肿瘤治疗中的思考和展望。

关键词: 溶瘤病毒, 免疫治疗, 恶性肿瘤, 免疫检查点抑制剂, 过继细胞疗法

Abstract:

The oncolytic virus (OV) therapy utilizes natural or genetically modified viruses to specifically target and infect tumor cells, leading to the destruction of cancer cells by the replication of the virus itself. This process also alters the immune microenvironment of the tumor transforming “cold” into “hot”, and mobilizes the body's immune system. The effectiveness of oncolytic viruses in anti-tumor therapy depends on factors such as the type of virus, host immunity and route of administration. Immunotherapy aims to activate the immune system and exert anti-tumor effect by relying on autoimmune function. With the development of genetic engineering technology, oncolytic viruses can enhance the anti-tumor effect through gene editing reconstruction, and can be used to treat tumors alone or in combination with other therapies. In view of the limited efficacy of single application of oncolytic virus therapy in clinic, the combination of oncolytic virus therapy and immunotherapy provides a new strategy for tumor treatment. This review started from the types of oncolytic viruses approved in the clinic, characteristics and its anti-tumor mechanisms. At the same time, it combed through the treatment of oncolytic viruses in the clinical trial stage, summarized the combined treatment strategies of oncolytic viruses, especially the combination of tumor immunotherapy represented by immune checkpoint inhibitor (ICI) and adoptive cell therapy (ACT), and put forward some thoughts and prospects of oncolytic viruses in the anti-tumor treatment in combination with the experience accumulated by the project team in the research of oncolytic viruses.

Key words: Oncolytic virus, Immunotherapy, Malignant tumor, Immune checkpoint inhibitor, Adoptive cell therapy

中图分类号:

R730.5

梁滢昀, 陈健华. 溶瘤病毒联合免疫治疗在恶性肿瘤治疗中的应用进展[J]. 中国癌症杂志, 2024, 34(7): 686-694.

LIANG Yingyun, CHEN Jianhua. Application progress of oncolytic virus combined with immunotherapy in the treatment of malignant tumors[J]. China Oncology, 2024, 34(7): 686-694.

图/表 1

表1

已登记的OV联合ICI或ACT治疗的临床研究"

Immunotherapy type	Oncolytic virus	Combination agent/target	Tumor type	Reference	Phase/status
ICI	Herpes simplex virus (RP1)	Nivolumab	Advanced and/or refractory solid tumors	NCT03767348	Phase Ⅰ/Ⅱ (recruiting)
	Herpes simplex virus type 1 (ONCR-177)	Pembrolizumab	Advanced and/or refractory cutaneous, subcutaneous or metastatic nodal solid tumors	NCT04348916	Phase Ⅰ (terminated)
	Herpes simplex virus type 1 (HF10)	Ipilimumab	Melanoma stage Ⅲ or Ⅳ	NCT03153085	Phase Ⅱ (completed)
	Herpes simplex virus type 1 (HF10)	Ipilimumab	Malignant melanoma	NCT02272855	Phase Ⅱ (completed)
	Adenovirus (TILT-123)	Pembrolizumab	Platinum-refractory and/or platinum-resistant ovarian carcinoma	NCT05271318	Phase Ⅰ (recruiting)
	Adenovirus (TILT-123)	Avelumab	Melanoma, HNSCC	NCT05222932	Phase Ⅰ (recruiting)
	Adenovirus (DNX-2401)	Pembrolizumab	Brain cancer	NCT02798406	Phase Ⅱ (completed)
	Adenovirus (Ad-MAGEA3)+MG1 Maraba oncolytic virus (MG1-MAGEA3)	Pembrolizumab	Metastatic NSCLC	NCT02879760	Phase Ⅰ/Ⅱ (completed)
	chimeric orthopoxvirus (CF33-hNIS)	Pembrolizumab	Advanced or metastatic solid tumors	NCT05346484	Phase Ⅰ (recruiting)
	Reovirus (REOLYSIN)	Pembrolizumab	Pancreatic adenocarcinoma	NCT02620423	Phase Ⅰ (completed)
	Reovirus (pelareorep)	Nivolumab+carfilzomib+dexamethasone	Recurrent plasma cell myeloma	NCT03605719	Phase Ⅰ (completed)
	Newcastle disease virus (MEDI5395)	Durvalumab	Advanced solid tumors	NCT03889275	Phase Ⅰ (completed)
	Vesicular stomatitis virus (Revottack)	Toripalimab	Advanced solid tumor	NCT05644509	Phase Ⅰ (not yet recruiting)
	Vesicular stomatitis virus (VSV-IFNβ-NIS)	Pembrolizumab	Refractory NSCLC and HNSCC	NCT03647163	Phase Ⅰ/Ⅱ (recruiting)
	Coxsackievirus (CVA21)	Ipilimumab	Uveal melanoma metastases to liver	NCT03408587	Phase Ⅰ (completed)
	Vaccinia virus (JX-594)	Cemiplimab	Renal cell carcinoma	NCT03294083	Phase Ⅰ/Ⅱ (active, not recruiting)
	Vaccinia virus (JX-594)	Durvalumab + tremelimumab	Refractory colorectal cancer	NCT03206073	Phase Ⅰ/Ⅱ (completed)
	Vaccinia virus (JX-594)	Ipilimumab	Metastatic/advanced solid tumors	NCT02977156	Phase Ⅰ (completed)
ACT	Adenovirus ( CAdVEC)	HER2-CAR-T	HER2 positive cancer	NCT03740256	Phase Ⅰ (recruiting)
	Vesicular stomatitis virus (OVV-01)	trained immunity NK (IBR900)	Advanced solid tumor, relapsed/refractory lymphoma	NCT05271279	Phase Ⅱ (terminated)
	Adenovirus (TILT-123)	Adoptive TIL	Metastatic melanoma	NCT04217473	Phase Ⅰ (recruiting)
	ALVAC MART-1	Anti-MART-1 F5 TCR cells	Metastatic melanoma	NCT00612222	Phase Ⅱ (terminated)

表1

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