溶瘤病毒靶向治疗肿瘤的策略

近年来,随着国内外几款溶瘤病毒制剂的相继上市,溶瘤病毒疗法成为肿瘤免疫治疗的焦点。溶瘤病毒可选择性感染并裂解肿瘤细胞,同时释放肿瘤相关抗原激活机体的抗肿瘤免疫反应,达到杀伤肿瘤细胞和抑制肿瘤生长的目的。溶瘤病毒对肿瘤的靶向杀伤作用决定了其安全性和溶瘤效果。为了开发出安全高效的溶瘤病毒,目前主要采用以下策略：利用某些病毒载体对肿瘤细胞的天然靶向性,使溶瘤病毒选择性地在肿瘤细胞内复制并杀伤肿瘤细胞;或者对病毒基因组进行缺失和插入等修饰,通过靶向肿瘤细胞特异性表面受体、胞内信号通路或者肿瘤微环境等提高溶瘤病毒的肿瘤靶向性。其中,肿瘤微环境中的低氧状态、新血管生成以及免疫抑制状态等都可成为溶瘤病毒的靶点。而溶瘤病毒通过表达细胞因子和免疫检查点抑制剂,或者与CAR-T细胞联合作用,靶向调节肿瘤微环境中免疫抑制状态,成为提高溶瘤病毒肿瘤靶向性的常用方法。本文将对以上溶瘤病毒靶向治疗肿瘤策略的研究进展进行综述。     

溶瘤病毒联合CAR-T细胞治疗实体瘤研究进展

嵌合抗原受体修饰的T细胞(chimeric antigen receptor T cells, CAR-T)疗法属于肿瘤免疫治疗的范畴。该疗法在血液系统恶性肿瘤治疗中表现优异,但在实体瘤治疗中存在诸多挑战。近年来,溶瘤病毒(oncolytic viruses, OVs)在针对黑色素瘤、脑胶质瘤等实体瘤适应证的临床试验中展现出良好的疗效。溶瘤病毒一方面选择性地在肿瘤细胞中复制杀伤肿瘤细胞,另一方面通过激活机体自身的免疫系统发挥抗肿瘤作用。因此,溶瘤病毒与免疫检查点抑制剂、肿瘤浸润淋巴细胞疗法(tumor infiltrating lymphocytes, TIL)等免疫疗法的联合应用也在广泛开展。目前研究表明,溶瘤病毒不仅能够增加CAR-T细胞的抗肿瘤活性,而且通过传递肿瘤相关抗原或特异性抗原来增强CAR-T细胞对肿瘤的杀伤作用,同时溶瘤病毒还可以帮助CAR-T细胞克服免疫抑制性的肿瘤微环境。两种疗法的联合应用在临床前研究中展现出了良好的疗效和安全性,能够解决CAR-T在实体瘤治疗领域的瓶颈,具有广阔的临床转化前景。本文就溶瘤病毒与CAR-T细胞联合治疗实体瘤的药效及相关机制研究展开论述...     

溶瘤病毒的免疫学机制及临床研究进展

溶瘤病毒（oncolytic virus,OVs）历经百年发展,应用于当前最具潜力的肿瘤免疫疗法。它主要是天然的或基因修饰的DNA病毒和RNA病毒。近年来随着基因工程技术的飞跃发展,经基因改造的溶瘤病毒在肿瘤治疗领域取得很大进展,很多不同类型的病毒（包括单纯疱疹病毒、腺病毒、痘病毒、麻疹病毒和呼肠孤病毒等）正处于临床前研究、临床试验阶段或已批准上市,显示了良好的安全性和临床疗效。普遍认为溶瘤病毒靶向杀伤肿瘤细胞是通过选择性在肿瘤细胞内自我复制,最终裂解肿瘤细胞,同时可激发机体的免疫应答反应,进而增强抗肿瘤免疫效果,靶向杀伤肿瘤细胞而对正常细胞无明显影响。运用基因重组技术将溶瘤病毒与免疫检查点相结合以及肿瘤免疫联合疗法的兴起和不断进步,使溶瘤病毒的应用更加广泛,但仍存在病毒靶向性、安全性、给药途径等瓶颈问题。本文综述了溶瘤病毒的发展史、病毒分类、不同类型溶瘤病毒产品的临床研究进展、溶瘤病毒靶向杀伤肿瘤的免疫学机制及未来发展面临的挑战与展望等。     

溶瘤腺病毒治疗肿瘤的研究进展

溶瘤腺病毒是一种改造过的能够选择性地在肿瘤细胞中复制,并能够杀死肿瘤细胞的腺病毒,目前已经应用于肿瘤治疗中。但是因为肿瘤的复杂性以及高突变性,所以提高溶瘤腺病毒对肿瘤的有效性,选择性和安全性成为了主要的研究方向。能够在体内正常表达shRNA、细胞因子、自杀基因、基质修饰蛋白等治疗性基因的溶瘤腺病毒具有比单纯的溶瘤腺病毒更强的抗肿瘤活性。而具有肿瘤特异性启动子,尤其是双调控启动子的溶瘤腺病毒对肿瘤细胞具有更强的选择性杀伤作用。另外用脂质体、PEG聚合物、纳米颗粒、多肽等包裹的溶瘤腺病毒能够减少病毒的免疫原性以及对肝脏的毒性,增强了全身给药途径的抗肿瘤活性。特别是用PEG连上抗体、小肽、细胞因子和配体,能显著提高溶瘤腺病毒的选择性。因此,整合病毒载体与非病毒载体的优点并与免疫治疗相结合,是一个很有希望的提高病毒靶向治疗效果的策略。     

溶瘤痘苗病毒对肿瘤细胞作用机制的研究进展

溶瘤病毒治疗,是指利用具有复制能力的病毒选择性地感染和摧毁癌细胞,而对正常细胞或组织影响很少甚至没有影响的一种癌症治疗方法.痘苗病毒在肿瘤的基因治疗应用研究中以其独特的优势而备受关注.痘苗病毒感染细胞后具有产生病毒颗粒快、宿主范围广、基因组容量大、安全性高、传播高效等优点.尤为重要的是,基于溶瘤痘苗病毒的天然特性或遗传工程的改造,溶瘤痘苗病毒可以选择性地在肿瘤细胞中复制并对其产生杀伤效果.痘苗溶瘤病毒引起肿瘤细胞裂解和死亡是由多种不同的机制引起的.本文就近年来溶瘤痘苗病毒对细胞作用机制和相关信号通路的影响作一简要综述.     

溶瘤病毒联合小分子抑制剂应用于肿瘤治疗的研究进展

溶瘤病毒因具有选择性杀伤肿瘤细胞的特性,已成为目前较有前景的肿瘤治疗类药物。溶瘤病毒疗法的安全性和有效性在临床中已得到证实,但由于恶性肿瘤高度的异质性和复杂性使得溶瘤病毒单药治疗肿瘤的效果受限,因此溶瘤病毒联合其他肿瘤治疗药物一起协同治疗肿瘤将是未来肿瘤治疗的重要发展方向之一,有望为肿瘤的治疗带来新的突破。新近研究表明,不同的小分子抑制剂可通过多种机制控制肿瘤生长,其在体外协同溶瘤病毒能达到更优的肿瘤治疗效果。本文就目前溶瘤病毒联合小分子抑制剂治疗肿瘤的研究进展进行综述。     

基因改造的溶瘤痘病毒在肿瘤治疗中的研究进展

目前,肿瘤的标准治疗包括手术、放射疗法、化学疗法、温热疗法和生物/免疫疗法。溶瘤病毒治疗,即利用病毒的复制能力,选择性感染和破坏肿瘤细胞,同时保留正常细胞和组织,是肿瘤生物/免疫治疗的一个新疗法。基因治疗一直是肿瘤生物治疗的重要策略,利用基因工程策略在溶瘤病毒载体上插入抗癌基因,将病毒治疗与基因治疗有机结合,成为具有很强杀伤作用的基因–病毒治疗手段。近年来,以溶瘤痘病毒为载体的肿瘤基因治疗受到较多关注,通过基因工程策略对痘病毒进行改造是提高其抗肿瘤作用的重要策略。目前,用于基因工程改造的溶瘤痘病毒主要有Wyeth株、WR(Western Reverse)株、Lister株、Copenhagen株和天坛株。该文就目前对痘病毒进行基因工程改造的常见形式以及经基因工程改造的痘病毒用于治疗肿瘤的研究进展作一综述。     

溶瘤病毒与肿瘤治疗

溶瘤病毒是目前恶性肿瘤治疗领域中较有前景的新型基因治疗药物,其通过选择性杀伤肿瘤细胞和诱导机体产生特异的抗肿瘤免疫两种途径来实现肿瘤靶向治疗的目的,从而达到较好的抗肿瘤效果。现对溶瘤病毒的溶瘤机制、临床研究、联合治疗和当前挑战及未来展望等方面进行综述。     

新城疫病毒抗肿瘤效应机制的研究现状

溶瘤病毒疗法是一种重要的抗癌手段。经研究,新城疫病毒(Newcastlediseasevirus,NDV)是一种非常有效的溶瘤病毒(oncolyticvirus,OV),它能选择性杀伤肿瘤细胞,对正常细胞几乎无影响。本文从NDV诱导肿瘤细胞发生凋亡、自噬、抑制细胞代谢、刺激机体免疫反应和诱导肿瘤细胞发生核糖体应激反应等方面综述了新城疫病毒的抗肿瘤效应机制,并着重探讨了NDV通过诱导核糖体压力应激反应调控肿瘤细胞翻译系统并诱导细胞发生凋亡的具体机制,旨在为今后NDV抗肿瘤作用的深入研究及靶向治疗癌症提供更加扎实丰富的理论基础。     

基于水疱性口炎病毒(VSV)的溶瘤病毒研究进展

溶瘤病毒利用肿瘤细胞抗病毒信号通路缺损或病毒受体过表达的特点,实现在其中选择性高复制进而杀伤肿瘤细胞,同时刺激机体产生特异性抗肿瘤免疫反应,是目前肿瘤治疗研究领域的热点。水疱性口炎病毒(vesicular stomatitis virus,VSV)能依赖肿瘤细胞干扰素信号通路的缺陷特异性靶向肿瘤细胞,具有复制高效、广泛组织嗜性、人群低致病性、基因组较小且易操纵等优势,是一种具有发展潜力的溶瘤病毒载体。对水疱性口炎病毒的病毒学特征以及目前基于VSV溶瘤病毒关于提高肿瘤选择性、延长半衰期、增强溶瘤效果的研究进展进行综述,为基于VSV溶瘤制剂的开发提供依据,为肿瘤治疗提供新的策略。     

Double trouble for tumours: Exploiting the tumour microenvironment to enhance anticancer effect of oncolytic viruses

Oncolytic viruses (OVs) are selected based on their ability to eliminate malignancies by direct infection and lysis of cancer cells. Originally, OVs were designed to target malignancies by taking advantage of the defects of cancer cells observed in vitro. Subsequent analysis of virus delivery and spread in vivo has demonstrated that the tumour microenvironment can impede the ability of OVs to effectively infect and spread. Despite this limitation, it is becoming increasingly evident that OVs are also able to take advantage of certain features of the tumour microenvironment. Currently, a growing body of the literature is delineating the complex interaction between OVs and the tumour microenvironment that results in an additional therapeutic activity; these viruses are able to target malignancies by rapidly altering the tumour microenvironment into a milieu that potentiates anticancer activity. Herein, we discuss strategies that capitalize on the multifaceted relationship between OVs and host–tumour interactions that enhance the toxicity of OVs to the tumour microenvironment.     

Oncolytic virotherapy for pancreatic ductal adenocarcinoma: A glimmer of hope after years of disappointment?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and highly lethal malignancies. Existing therapeutic interventions have so far been unsuccessful in improving prognosis, and survival remains very poor. Oncolytic virotherapy represents a promising, yet not fully explored, alternative strategy for the treatment of PDAC. Oncolytic viruses (OVs) infect, replicate within and lyse tumor cells specifically and stimulate antitumor immune responses. Multiple challenges have hampered the efficacy of oncolytic virotherapy for PDAC, the most significant being the desmoplastic and immunosuppressive pancreatic tumor microenvironment (TME). The TME limits the access of therapeutic drugs and the infiltration of effector T cells and natural killer (NK) cells into the tumor mass. Additionally, cancer cells promote the secretion of immunosuppressive factors and develop mechanisms to evade the host immune system. Because of their oncolytic and immune-stimulating properties, OVs are the ideal candidates for counteracting the pancreatic immunosuppressive TME and for designing combination therapies that can be clinically exploited in clinical trials that seek to improve the prognosis of PDAC.     

The two-faces of NK cells in oncolytic virotherapy

Oncolytic viruses (OVs) are immunotherapeutics capable of directly killing cancer cells and with potent immunostimulatory properties. OVs exert their antitumor effect, at least partially, by activating the antitumor immune response, of which NK cells are an important component. However, if on the one hand increasing evidence revealed that NK cells are important mediators of oncolytic virotherapy, on the other hand, NK cells have evolved to fight viral infections, and therefore they can have a detrimental effect for the efficacy of OVs. In this review, we will discuss the dichotomy between the antitumor and antiviral functions of NK cells related to oncolytic virotherapy. We will also review NK cell-based and OV-based therapies, engineered OVs aimed at enhancing immune stimulation, and combination therapies involving OVs and NK cells currently used in cancer immunotherapy.     

Oncolytic viruses for the treatment of neuroendocrine tumors

Oncolytic viruses are emerging as anticancer agents, and they have also shown great promise for use against neuroendocrine tumors. Many viruses have a natural tropism for replication in tumor cells. Others can be genetically engineered to selectively kill tumor cells. Viruses have some advantages as therapeutic agents over current cytotoxic drugs and small molecules. They replicate in tumor cells and thereby increase in number over time leading to increased dosage. They are immunogenic and can alter the immunosuppressive tumor microenvironment and activate immune effector cells. They have also been shown to be able to kill drug-resistant cancer stem cells. This article reviews the recent literature on oncolytic viruses used so far for neuroendocrine tumors and indicates important issues to focus on in the future.     

Current landscape and perspective of oncolytic viruses and their combination therapies

Oncolytic virotherapy has become an important strategy in cancer immunotherapy. Oncolytic virus (OV) can reshape the tumor microenvironment (TME) through its replication-mediated oncolysis and transgene-produced anticancer effect, inducing an antitumor immune response and creating favorable conditions for the combination of other therapeutic measures. Extensive preclinical and clinical data have suggested that OV-based combination therapy has definite efficacy and promising prospects. Recently, several clinical trials of oncolytic virotherapy combined with immunotherapy have made breakthroughs. This review comprehensively elaborates the OV types and their targeting mechanisms, the selection of anticancer genes armed in OVs, and the therapeutic modes of action and strategies of OVs to provide a theoretical basis for the better design and construction of OVs and the optimization of OV-based therapeutic strategies.     

Vesicular stomatitis virus sensitizes immunologically cold tumors to checkpoint blockade by inducing pyroptosis

BackgroundTraditionally, vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) are thought to kill tumors by inducing apoptosis. However, cell apoptosis leads to immune quiescence, which is incompatible with the ability of OVs to activate the antitumor immune microenvironment. Thus, studying OVs-mediated oncolytic mechanisms is of great importance for the clinical application of OVs.MethodsWe examined the pyroptosis in tumor cells and tissues by morphological observation, Lactate Dehydrogenase (LDH) assay, frozen section observation, and western-blotting techniques. The critical role of GSDME in VSV-induced pyroptosis was confirmed by CRISPR/Cas9 technique. VSV virotherapy-recruited cytotoxic lymphocytes in the tumors were examined by flow cytometry assay. VSV-activated antitumor immunity was further enhanced by the co-administration with anti-PD-1 antibody.ResultsHere, we observed that VSV was able to trigger tumor pyroptosis through Gasdermin E (GSDME) in tumor cells, human tumor samples, and tumor-bearing mouse models. Importantly, the effectiveness of VSV-based virotherapy is highly dependent on GSDME, as depletion of GSDME not only reverses VSV-induced tumor-suppressive effects but also diminishes the ability of VSV to activate antitumor immunity. Notably, VSV treatment makes immunologically ‘cold’ tumors more sensitive to checkpoint blockade.ConclusionsOncolytic VSV induces tumor cell pyroptosis by activating GSDME. GSDME is critical in recruiting cytotoxic T lymphocytes in the context of VSV therapy, which can switch immunologically ‘cold’ tumors into ‘hot’ and enhance immune checkpoint therapy efficacy.     

Oncolytic virotherapy: molecular targets in tumor-selective replication and carrier cell-mediated delivery of oncolytic viruses

Tremendous advances have been made in developing oncolytic viruses (OVs) in the last few years. By taking advantage of current knowledge in cancer biology and virology, specific OVs have been genetically engineered to target specific molecules or signal transduction pathways in cancer cells in order to achieve efficient and selective replication. The viral infection and amplification eventually induce cancer cells into cell death pathways and elicit host antitumor immune responses to further help eliminate cancer cells. Specifically targeted molecules or signaling pathways (such as RB/E2F/p16, p53, IFN, PKR, EGFR, Ras, Wnt, anti-apoptosis or hypoxia) in cancer cells or tumor microenvironment have been studied and dissected with a variety of OVs such as adenovirus, herpes simplex virus, poxvirus, vesicular stomatitis virus, measles virus, Newcastle disease virus, influenza virus and reovirus, setting the molecular basis for further improvements in the near future. Another exciting new area of research has been the harnessing of naturally tumor-homing cells as carrier cells (or cellular vehicles) to deliver OVs to tumors. The trafficking of these tumor-homing cells (stem cells, immune cells and cancer cells), which support proliferation of the viruses, is mediated by specific chemokines and cell adhesion molecules and we are just beginning to understand the roles of these molecules. Finally, we will highlight some avenues deserving further study in order to achieve the ultimate goals of utilizing various OVs for effective cancer treatment.     

The combination therapy of oncolytic HSV-1 armed with anti-PD-1 antibody and IL-12 enhances anti-tumor efficacy

Cancer immunotherapy is a new therapeutic strategy for cancer treatment that targets tumors by improving or restoring immune system function. Therapies targeting immune checkpoint molecules have exerted potent anti-tumor effects and prolonged the overall survival rate of patients. However, only a small number of patients benefit from the treatment. Oncolytic viruses exert anti-tumor effects by regulating the tumor microenvironment and affecting multiple steps of tumor immune circulation. In this study, we engineered two oncolytic viruses that express mouse anti-PD-1 antibody (VT1093M) or mouse IL-12 (VT1092M). We found that both oncolytic viruses showed significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Importantly, the intratumoral combined injection with VT1092M and VT1093M inhibited growth of the primary tumor, prevented growth of the contralateral untreated tumor, produced a vaccine-like response, activated antigen-specific T cell responses and prolonged the overall survival rate of mice. These results indicate that combination therapy with the engineered oncolytic virus may represent a potent immunotherapy strategy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.