Abstract

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.

中文翻译：

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[溶瘤病毒疗法与 CAR T/NK 细胞疗法联合治疗癌症]。

摘要

多行证据表明，基于 CAR-T 细胞的疗法和溶瘤病毒疗法在免疫活性和免疫缺陷小鼠模型中均表现出稳健的性能。还报道了将这些治疗平台结合起来的罕见但非常成功的尝试。有趣的是，这两种方法在人体试验中都显示出明显的疗效，尽管这些试验仅限于少数恶性肿瘤。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非常有效，而施用溶瘤病毒可在黑色素瘤（Imlygic 和 Rigvir）和鼻咽癌（Oncorine）患者中产生明显的反应。众所周知，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和不断增加的免疫反应的限制，并且需要相对功能性的免疫系统，这对于癌症患者来说并不常见，目前的抗肿瘤治疗方案. 另一方面，当前 CAR-T 细胞疗法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，更不用说难以接受的高成本了。值得注意的是，结合这两种方法可能有助于解决各自的瓶颈。即，由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；结合病毒和 CAR 介导的细胞毒性可以确保免疫原性细胞碎片的产生和肿瘤新抗原的有效呈递，并有效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 和病毒分解方法的组合似乎既合乎逻辑又极具前景。