Kochneva G V, Sivolobova G F, Tkacheva A V, Gorchakov A A, Kulemzin S V
State Research Center of Virology and Biotechnology "Vector", Koltsovo, Novosibirsk oblast, 630559 Russia.
Institute of Molecular and Cellular Biology, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia.
Mol Biol (Mosk). 2020 Jan-Feb;54(1):3-16. doi: 10.1134/S0026893320010100.
Multiple lines of evidence indicate that CAR-T cell based therapy and oncolytic virotherapy display robust performance in both immunocompetent and immunodeficient mouse models. Rare, yet highly successful attempts to combine these therapeutic platforms have also been reported. Interestingly, both approaches have shown pronounced efficacy in human trials, albeit these were limited to just a handful of malignancies. Specifically, CD19-specific CAR-T cell products (Kymriah and Yescarta) have been highly effective against B cell lymphomas and leukemias, whereas administering oncolytic viruses resulted in pronounced responses in melanoma (Imlygic and Rigvir) and nasopharyngeal carcinoma (Oncorine) patients. It is well established that efficacy of virotherapy as a standalone approach is largely restricted by the pre-existing and mounting immune response against viral antigens, and requires a relatively functional immune system, which is not typical for cancer patients, with the current antitumor therapy schemes. On the other hand, the most important challenges faced by the current CAR-T cell therapy formats include the lack of targetable tumor-specific surface antigens, tumor cell heterogeneity, and immunosuppressive tumor microenvironment, not to mention the unacceptably high costs. Remarkably, combining the two approaches may help address their individual bottlenecks. Namely, local acute inflammatory reaction induced by the viral infection may reverse tumor-associated immunosuppression and lead to more efficient homing and penetration of CAR-expressing lymphocytes into the tumor stroma; combined viral and CAR-mediated cytotoxicity may ensure the production of immunogenic cell debris and efficient presentation of tumor neoantigens, and potently recruit the patient's own bystander immune cells to attack cancer cells. Thus, testing the combinations of CAR-based and virolytic approaches in the clinical setting appears both logical and highly promising.
多条证据表明，基于嵌合抗原受体T细胞（CAR-T）的疗法和溶瘤病毒疗法在免疫健全和免疫缺陷小鼠模型中均表现出强大的性能。也有报道称，将这两种治疗平台结合的尝试虽罕见但非常成功。有趣的是，这两种方法在人体试验中均显示出显著疗效，尽管这些试验仅限于少数几种恶性肿瘤。具体而言，CD19特异性CAR-T细胞产品（Kymriah和Yescarta）对B细胞淋巴瘤和白血病具有高效，而施用溶瘤病毒则在黑色素瘤（Imlygic和Rigvir）和鼻咽癌（安柯瑞）患者中产生了显著反应。众所周知，溶瘤病毒疗法作为一种独立方法的疗效在很大程度上受到针对病毒抗原的预先存在且不断增强的免疫反应的限制，并且需要相对功能正常的免疫系统，而在当前的抗肿瘤治疗方案下，癌症患者通常并非如此。另一方面，当前CAR-T细胞治疗形式面临的最重要挑战包括缺乏可靶向的肿瘤特异性表面抗原、肿瘤细胞异质性和免疫抑制性肿瘤微环境，更不用说高得令人难以接受的成本了。值得注意的是，将这两种方法结合可能有助于解决它们各自的瓶颈问题。也就是说，病毒感染引起的局部急性炎症反应可能会逆转肿瘤相关的免疫抑制，并导致表达CAR的淋巴细胞更有效地归巢和渗透到肿瘤基质中；病毒和CAR介导的联合细胞毒性可能确保产生免疫原性细胞碎片并有效呈递肿瘤新抗原，并有力地招募患者自身的旁观者免疫细胞来攻击癌细胞。因此，在临床环境中测试基于CAR的方法和溶瘤方法的组合似乎既合乎逻辑又极具前景。
