溶瘤病毒在乳腺癌治疗中的研究进展

乳腺癌是女性最常见的恶性肿瘤之一，尽管现有治疗手段对乳腺癌的治疗效果已有较大改进，但对晚期及三阴性乳腺癌仍有局限性，因此需要探索新的治疗方法。溶瘤病毒（oncolytic viruses，OVs）疗法是肿瘤免疫疗法的一种，OVs通过靶向作用可特异性地杀伤肿瘤细胞、抑制血管生成、调节肿瘤微环境、促进抗肿瘤免疫。目前，乳腺癌治疗中使用的OVs种类较多，其有效性及安全性尚可，在联合免疫治疗时有协同促进作用。本文将就OVs在乳腺癌治疗中的主要研究进展进行综述。      

基于EB病毒的肿瘤靶向治疗策略

爱泼斯坦-巴尔病毒(EBV)相关肿瘤中存在EBV及其产物,为特异性杀伤肿瘤细胞提供了理想靶点。通过抑制EBV转化蛋白表达,靶向EBV复制启动元件,诱导EBV裂解感染以及EBV特异性免疫治疗等途径,为肿瘤治疗提供了新的以病毒为靶点的治疗策略。     

基于EB病毒的肿瘤靶向治疗策略

爱泼斯坦-巴尔病毒（EBV）相关肿瘤中存在EBV及其产物，为特异性杀伤肿瘤细胞提供了理想靶点。通过抑制EBV转化蛋白表达，靶向EBV复制启动元件，诱导EBV裂解感染以及EBV特异性免疫治疗等途径，为肿瘤治疗提供了新的以病毒为靶点的治疗策略。     

溶瘤病毒治疗恶性肿瘤研究进展

据统计,约l5%的人类肿瘤与病毒感染有关.一些病毒可通过表达蛋白或携带遗传调控元件,干扰正常细胞生长周期,导致细胞转化和肿瘤发生;另一方面,许多病毒又可特异性地感染肿瘤细胞并在细胞内复制,杀伤肿瘤细胞,这类病毒称为溶瘤病毒(oncolytic virus,OV).溶瘤病毒能够选择性地在肿瘤细胞中复制,造成细胞病理效应和机体免疫反应,导致肿瘤细胞的裂解死亡,同时对正常细胞和组织却没有破坏作用或影响较小.     

溶瘤腺病毒及其靶向治疗肿瘤研究进展

溶瘤腺病毒是对已知腺病毒进行改造得到的能对肿瘤基因表型的缺陷产生特异性杀伤作用及起到抗肿瘤药物的靶向性载体作用的病毒.目前通过对腺病毒5的特定基因片段的处理得到了H101和dl1520等生物制品,针对肿瘤细胞的p53基因表达缺陷,特异性识别肿瘤并在肿瘤细胞内进行繁殖和裂解肿瘤细胞.这些生物制品可以作为载体携带抗肿瘤基因,产生更加强大的抗肿瘤作用.     

溶瘤单纯疱疹病毒治疗肿瘤的研究进展

肿瘤的生物治疗已成为继手术、化疗、放疗之后的第四种肿瘤治疗手段。溶瘤病毒是一种大有发展潜力的生物治疗手段,它能选择性感染肿瘤细胞并在肿瘤细胞中复制,最终裂解、杀死肿瘤细胞,并释放出子代病毒颗粒进一步感染周围的肿瘤细胞,此过程还有助于肿瘤相关抗原的释放。近年来研究人员对单纯疱疹病毒的研究越来越广泛,尤其是Ⅰ型单纯疱疹病毒,美国FDA已批准了其中的一种（T-VEC）在黑色素瘤患者中的临床应用。目前,Ⅱ型单纯疱疹病毒也逐步显示出其自身的优势,部分研究初步揭示了该病毒的潜在价值,使其有望成为病毒疗法中更为重要的一员,本文就溶瘤单纯疱疹病毒在肿瘤治疗中的应用进行综述。     

靶向肿瘤的溶瘤腺病毒制备策略的研究进展

溶瘤腺病毒是指经过基因工程改造的腺病毒,其能够选择性地在肿瘤细胞中复制和表达,从而溶解肿瘤细胞;其可经过基因和衣壳蛋白层面的改造,特异性地结合和杀伤肿瘤细胞。自1996 年世界上第一例溶瘤腺病毒ONXY-015 开展临床研究以来,腺病毒在国内外广泛地应用于科学研究及转化应用,已有多个国家批准其在临床肿瘤治疗中使用,使用范围涉及到多种实体瘤。溶瘤腺病毒的改造方式多种多样,本文对溶瘤腺病毒治疗肿瘤的改造方法,如腺病毒的包膜蛋白进行修饰、腺病毒的结构基因进行改造、插入肿瘤特异性启动子、携带治疗基因与携带短发夹RNA和包括溶瘤病毒的多措施联合等研究进展作一综述。     

肿瘤的“自杀基因”疗法研究进展

将“自杀基因”导入肿瘤细胞而将前体药物在肿瘤细胞内代谢为毒性产物进而杀伤肿瘤细胞的“自杀基因”疗法是肿瘤基因治疗中引人注目的途径之一。细胞的自杀机制是设计该疗法的基础，“自杀基因”有多种，包括ｔｋ及ＣＤ等，将肿瘤细胞特异的调控元件或转录元件下自杀基因相结合可使“自杀基因”特异地在肿瘤细胞中表达，从而选择性地杀伤肿瘤细胞。美国ＮＩＨ已批准ＨＳＶ－ｔｋ基因转染疗法用于脑瘤等的临床试治。     

CD基因靶向治疗与放疗联合应用的研究进展

基因治疗作为治疗恶性肿瘤的1种新手段，正愈来愈受到重视和关注，肿瘤基因治疗的原理是将目的基因用基因转移技术导入靶细胞，使其表达此基因而获得特定的功能和效应．继而执行或介导对肿瘤的杀伤和抑制作用，最终达到直接或是间接杀灭肿瘤细胞的目的。自杀基因疗法：又称病毒介导的酶-药物前体疗法（virys—directed enzyme prodrug therapy，VDEPT）．     

溶瘤病毒疗法的研究现状与展望

针对癌症的传统治疗手段主要有手术治疗、化疗、放疗等。这些方法虽然能在一定程度上控制肿瘤生长，但也存在一定的技术局限性。溶瘤病毒疗法作为一种新型的肿瘤细胞生物疗法，为恶性肿瘤的治疗带来了新的发展希望。溶瘤病毒能够在不影响正常细胞的情况下，发挥较强的肿瘤抑制和杀伤作用，同时通过免疫诱导促使机体产生抗肿瘤免疫反应，进一步提高对肿瘤细胞的杀伤效果。然而，由于病毒自身存在较强的免疫原性，静脉注射后会引发机体产生不同程度的免疫应答，并且溶瘤病毒的肿瘤靶向性和单独治疗能力有限，使得其最终的肿瘤治疗效果并不理想。研究者通过设计并构建不同类型的载体来装载病毒，以封闭其固有的免疫原性，延长其血液循环时间的同时，进一步提高其对恶性肿瘤的靶向性，并在此基础上将溶瘤病毒与其他肿瘤治疗手段结合，进而增强溶瘤病毒的肿瘤治疗效果。本文将重点围绕如何有效构建溶瘤病毒载体及联合其他肿瘤治疗手段以提高溶瘤病毒的肿瘤治疗效果，对近期相关研究进展进行综述介绍。     

Effect of hepatitis B virus DNA replication level and anti-HBV therapy on microvascular invasion of hepatocellular carcinoma

Background

With few exceptions, current chemotherapy and radiotherapy protocols only obtain a slightly prolonged survival with severe adverse effects in patients with advanced solid tumors. In particular, most solid malignancies not amenable to radical surgery still carry a dismal prognosis, which unfortunately is also the case for relapsing disease after surgery. Even though targeted therapies obtained good results, clinical experience showed that tumors eventually develop resistance. On the other hand, earlier attempts of cancer immunotherapy failed to show consistent efficacy. More recently, a deeper knowledge of immunosuppression in the tumor microenvironment (TME) allowed the development of effective drugs: in particular, monoclonal antibodies targeting the so-called immune checkpoint molecules yielded striking and lasting effects in some tumors. Unfortunately, these monoclonal antibodies are not effective in a majority of patients and are ineffective in several solid malignancies. Furthermore, due to their mechanism of action, checkpoint inhibitors often elicit autoimmune-like disease.

Main body

The use of viruses as oncolytic agents (OVs) was considered in the past, while only recently OVs revealed a connection with immunotherapy. However, their antitumoral potential has remained largely unexplored, due to safety concerns and some limitations in the techniques to manipulate viruses. OV research was recently revived by a better knowledge of viral/cancer biology and advances in the methodologies to delete virulence/immune-escape related genes from even complex viral genomes or “to arm” OVs with appropriate transgenes. Recently, the first oncolytic virus, the HSV-1 based Talimogene Laherparepvec (T-VEC), was approved for the treatment of non-resectable melanoma in USA and Europe.

Conclusion

OVs have the potential to become powerful agents of cancer immune and gene therapy. Indeed, in addition to their selective killing activity, they can act as versatile gene expression platforms for the delivery of therapeutic genes. This is particularly true for viruses with a large DNA genome, that can be manipulated to address the multiple immunosuppressive features of the TME. This review will focus on the open issues, on the most promising lines of research in the OV field and, more in general, on how OVs could be improved to achieve real clinical breakthroughs in cancers that are usually difficult to treat by immunotherapy.

     

自然杀伤细胞治疗急性髓系白血病的研究进展

自然杀伤细胞(natural killer cell,NK)为一种存在于天然免疫系统中的淋巴细胞,具有杀伤肿瘤细胞和抗病毒感染的能力,在天然免疫和过继免疫治疗中发挥重要作用。随着NK细胞的特征和功能越来越被熟知,其已被广泛应用于临床抗肿瘤治疗,特别是血液系统恶性肿瘤如急性髓系白血病(acute myeloid leukemia,AML)、淋巴瘤等治疗。目前,基于NK细胞的免疫治疗主要包括自体NK细胞输注、异体NK细胞输注、嵌合抗原修饰NK(chimeric antigen receptor,CAR)细胞输注以及基于NK细胞的其他免疫治疗等。以NK细胞为基础的免疫治疗旨在增强NK细胞的抗肿瘤能力以及克服肿瘤免疫逃逸。随着研究进展,NK细胞将成为治疗AML的有效方法。     

The role of natural killer cells in combinatorial anti-cancer therapy using Sindbis viral vectors and irinotecan

Oncolytic viruses (OVs) have shown great anti-cancer potential in animal models, but only modest success in early clinical trials. A better understanding of the mechanisms underlining OV efficacy is needed to resolve this discrepancy. In the clinic, OV therapy will likely be combined with traditional chemotherapy, underscoring the need to also evaluate the interactions between these therapeutic modalities. Here we show that combining Sindbis viral vector therapy with the topoisomerase inhibitor irinotecan (CPT-11) results in the long-term survival of about 35% of SCID mice bearing aggressively growing ES2 human ovarian cancer. Single-agent treatments did not result in long-term survival. Flow cytometry analysis, bioluminescent imaging and survival experiments revealed that Sindbis and CPT-11 utilize non-overlapping natural killer (NK)-cell-dependent and -independent anti-cancer mechanisms, respectively. Notably, the combinatorial therapy was only effective in the presence of NK cells. These results highlight the hidden role of immune cell activation in combinatorial cancer therapy involving OVs and provide a potential method for tackling tumor cell resistance to cancer therapy while limiting treatment-related side effects.     

Mesenchymal stem cell carriers enhance anti-tumor efficacy of oncolytic virotherapy

Oncolytic viruses (OVs) specifically infect, replicate and eventually destroy tumor cells, with no concomitant toxicity to adjacent normal cells. Furthermore, OVs can regulate tumor microenvironments and stimulate anti-tumor immune responses. Mesenchymal stem cells (MSCs) have inherent tumor tropisms and immunosuppressive functions. MSCs carrying OVs not only protect viruses from clearing by the immune system, but they also deliver the virus to tumor lesions. Equally, cytokines released by MSCs enhance anti-tumor immune responses, suggesting that MSCs carrying OVs may be considered as a promising strategy in enhancing the anti-tumor efficacies of virotherapy. In the present review, preclinical and clinical studies were evaluated and discussed, as well as the effectiveness of MSCs carrying OVs for tumor treatment.     

Survivin promoter-regulated oncolytic adenovirus with Hsp70 gene exerts effective antitumor efficacy in gastric cancer immunotherapy

Gene therapy is a promising adjuvant therapeutic strategy for cancer treatment. To overcome the limitations of current gene therapy, such as poor transfection efficiency of vectors, low levels of transgene expression and lack of tumor targeting, the Survivin promoter was used to regulate the selective replication of oncolytic adenovirus in tumor cells, and the heat shock protein 70 (Hsp70) gene was loaded as the anticancer transgene to generate an AdSurp-Hsp70 viral therapy system. The efficacy of this targeted immunotherapy was examined in gastric cancer. The experiments showed that the oncolytic adenovirus can selectively replicate in and lyse the Survivin-positive gastric cancer cells, without significant toxicity to normal cells. AdSurp-Hsp70 reduced viability of cancer cells and inhibited tumor growth of gastric cancer xenografts in immuno-deficient and immuno-reconstruction mouse models. AdSurp-Hsp70 produced dual antitumor effects due to viral replication and high Hsp70 expression. This therapeutic system used the Survivin promoter-regulated oncolytic adenovirus vector to mediate targeted expression of the Hsp70 gene and ensure safety and efficacy for subsequent gene therapy programs against a variety of cancers.     

Bispecific T cell engagers and their synergistic tumor immunotherapy with oncolytic viruses

Tumor immunotherapy, especially T cell based therapy, is becoming the main force in clinical tumor therapies. Bispecific T cell engager (BiTE) uses the single chain variable fragments (scFv) of two antibodies to redirect T cells to kill target cells. BiTEs for hematologic tumors has been approved for clinical use, and BiTEs for solid tumors showed therapeutic effects in clinical trials. Oncolytic viruses (OVs) of the adenovirus expressing p53 and herpes simplex virus expressing GM-CSF was approved for clinical use in 2003 and 2015, respectively, while other OVs showed therapeutic effects in clinical trials. However, BiTE and Oncolytic virus (OV) have their own limitations. We propose that OV-BiTE has a synergistic effect on tumor immunotherapy. Feng Yu et al. designed the first OV-BiTE in 2014, which remarkably eradicated tumors in mice. Here we review the latest development of the structure, function, preclinical studies and/or clinical trials of BiTE and OV-BiTE and provide perspective views for optimizing the design of OV-BiTE. There is no doubt that OV-BiTE is becoming an exciting new platform for tumor immunotherapy and will enter clinical trial soon. Exploring the therapeutic effects and safety of OV-BiTE for synergistic tumor immunotherapy will bring new hope to tumor patients.     

Oncolytic Maraba Virus MG1 as a Treatment for Sarcoma

The poor prognosis of patients with advanced bone and soft‐tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre‐clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side‐by‐side comparison of clinically relevant OV platforms has not been performed. Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes‐simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long‐lasting cures in sarcoma‐bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge. This study opens the door for the use of MG1‐based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy.     

SBRT联合免疫治疗的机制及研究进展

近年来,大量临床前和临床研究表明,SBRT除直接杀伤肿瘤细胞外,还能导致肿瘤细胞免疫原性死亡,释放大量肿瘤相关抗原(TAA)及危险相关模式分子(DAMPs)形成肿瘤原位疫苗。通过激活的抗原提呈细胞交叉致敏引流淋巴结内的CD8(+) T细胞。SBRT能介导肿瘤局部和全身系统性的抗肿瘤免疫反应,与免疫治疗结合,还可以引发远位效应。SBRT同时能改善肿瘤免疫抑制微环境,增加肿瘤对免疫治疗的敏感性。本文对SBRT联合肿瘤免疫治疗的协同作用机制的研究进展进行综述。     

应用病毒治疗结直肠癌的研究进展*

基于病毒的抗肿瘤治疗是一种新兴的生物治疗方式,病毒载体感染肿瘤组织,引起溶瘤效应,制成疫苗激活体内抗肿瘤免疫,搭载基因行癌症的基因治疗。随着对病毒的不断改造,各类病毒治疗肿瘤更趋于安全和高效,同时,病毒载体与现有的抗肿瘤疗法合理联用,可提高治疗效果。因此,基于病毒的抗肿瘤治疗将作为极具潜力的方法而逐渐引起人们的重视。本文就近些年各种病毒在治疗结直肠癌中的研究进展做一综述。