编码免疫检查点抑制剂的溶瘤病毒:免疫联合治疗新思路

Oncolytic Viruses Encoding Immune Checkpoint Inhibitors:a New Approach to Immunotherapy Combinatorial Treatment

近年来,继手术、放化疗、靶向治疗后,免疫疗法的兴起为肿瘤治疗领域带来了革命性的变化。在诸多肿瘤免疫治疗方法当中,免疫检查点抑制剂以其突出的肿瘤免疫逃逸抑制能力和临床生存获益,被认为最具发展潜力的肿瘤免疫疗法之一。然而,由肿瘤微环境塑造的低免疫原性,被认为是阻碍免疫治疗发展的关键因素。溶瘤病毒是一类能够选择性感染癌细胞的病毒,能通过直接裂解杀死癌细胞,进而加强肿瘤抗原呈递,招募和激活特异性与先天性免疫细胞,将“冷肿瘤”转化为“热肿瘤”,使得ICI的作用基础(细胞毒性T细胞浸润增加),促进ICI发挥作用。在基因编辑技术高度发达的今天,经过基因改造,设计携带免疫检查点抑制剂分子编码基因的溶瘤病毒,使其在肿瘤当中特异性表达免疫检查点抑制剂,为溶瘤病毒和免疫检查点抑制剂的联合治疗开辟了新思路。这一新策略不仅能够发挥二者在免疫治疗机制层面相互补足的优势,还能够提高免疫检查点抑制剂在肿瘤微环境的特异性表达,规避其不良反应,开拓了以溶瘤病毒基因工程为基础的免疫治疗新思路。目前,该策略在总体生存期的提高、肿瘤生长的抑制、再次激发后记忆T细胞对肿瘤的排斥、T细胞(CD4^(+)、CD8^(+)和CD3^(+)T细胞)的浸润提升等方面都呈现可期效益,并具备建立更持久的特异性免疫、灵活的免疫检查点抑制剂编码表达、医疗成本低等优点,具有广阔开发前景。然而,目前此类研究尚未进入临床阶段,且其本身在安全性、有效性等方面尚存缺陷,是值得深入挖掘研究肿瘤治疗策略之一。

In recent years,following surgery,radiotherapy,chemotherapy,and targeted therapy,the rise of immunotherapy has brought revolutionary changes to the field of cancer treatment.Oncolytic viruses are a class of viruses that can selectively infect cancer cells.They can kill cancer cells through direct lysis and also alter the tumor microenvironment(TME)by enhancing tumor antigen presentation,activating the body’s innate and specific immunity.They are one of the emerging immunotherapies in recent years.Among the various cancer immunotherapy methods,immune checkpoint inhibitors,with their outstanding ability to suppress tumor immune evasion,are considered one of the most promising cancer immunotherapy approaches in terms of clinical survival benefits.However,the low immunogenicity shaped by the tumor microenvironment is believed to be a key factor hindering the development of immunotherapy.Correspondingly,oncolytic viruses can transform“cold tumors”into“hot tumors”by killing cancer cells,presenting antigens,recruiting and activating specific and innate immune cells.This significantly increases the infiltration of cytotoxic T cells,which promotes the effectiveness of immune checkpoint inhibitors(ICI).In today’s highly advanced gene editing technology,through genetic modification,oncolytic viruses designed to carry genes encoding immune checkpoint inhibitor molecules can specifically express immune checkpoint inhibitors within tumors.This paves the way for a new approach to combined treatment with oncolytic viruses and immune checkpoint inhibitors.This new strategy not only leverages the complementary advantages of both in terms of the mechanisms of immunotherapy but also enhances the specific expression of immune checkpoint inhibitors and avoids their adverse effects,opening up a new avenue for immunotherapy based on oncolytic virus gene engineering.Currently,this strategy shows promising benefits in terms of overall survival improvement,tumor growth suppression,reinvigoration of memory T cells against tumors,and enhancement of infiltration of T cells(CD4^(+),CD8^(+),and CD3^(+)T cells).It also offers the potential to establish more durable specific immunity,flexible expression of immune checkpoint inhibitors,and lower medical costs.It has broad prospects for development and application.However,the research has not yet entered the clinical stage,and there are still deficiencies in safety,effectiveness,etc.Therefore,it is one of the hot medical strategies worth further exploration,research,and application.