溶瘤病毒与泌尿系统恶性肿瘤治疗进展

溶瘤病毒(Oncolytic virus)是一种利用自身在肿瘤细胞内复制最终导致细胞溶解和死亡的病毒,是目前各种癌症治疗中特别有希望的实验性治疗方法.本文就溶瘤病毒和泌尿系统恶性肿瘤的治疗进展作一综述.     

溶瘤病毒在膀胱癌治疗中的研究进展

膀胱癌是最常见的泌尿系统恶性肿瘤之一, 目前推荐以手术治疗、放化疗等多方式的综合性治疗, 但总体预后较差, 临床上迫切需要更有效的药物, 而溶瘤病毒为此提供了新的契机。溶瘤病毒代表了一种尖端且具有潜力的癌症免疫治疗方法。它是一种能够选择性地感染和破坏肿瘤细胞的病毒, 杀伤力大并且可同时避免伤害正常细胞的特点。目前溶瘤病毒对于膀胱癌的治疗尤其是在非浸润性膀胱癌方面有了重大的突破, 并在多项临床试验中表达出了有效性和安全性。本文将对几种应用广泛的溶瘤病毒的种类, 改造方法, 抑癌机制及相关的信号表达通路在膀胱癌的研究现状和进展进行综述。     

溶瘤病毒在脑胶质瘤治疗中的研究进展

近年来, 溶瘤病毒在脑胶质瘤治疗中的应用成为研究热点, 关于溶瘤病毒的改造、疗效和安全性等临床研究结果的发布, 使脑胶质瘤治疗的发展前景充满希望。目前, 由单纯疱疹病毒改造的溶瘤病毒在日本已获得批准用于治疗恶性脑胶质瘤, 为脑胶质瘤的临床治疗带来了新模式。重组脊髓灰质炎病毒、腺病毒联合免疫检查点抑制剂治疗脑胶质瘤的临床试验结果均获得了良好的生存结果。同时, 溶瘤病毒治疗过程中也存在给药途径的选择和治疗效果的持续性等问题, 尚需进一步的基础和临床研究来提高和优化溶瘤病毒用于脑胶质瘤的疗效和治疗策略。     

胃壁富于细胞性神经鞘瘤误诊为胃间质瘤的临床分析

富于细胞性神经鞘瘤是一种少见的周围神经良性肿瘤.该肿瘤主要由交织束状排列的梭形细胞组成,缺乏典型神经鞘瘤中常见的网状区和栅栏状排列等结构,瘤细胞较丰富,核染色质粗、深染,并可显示一定的多形性.因此,本病极易被误诊为各种类型的梭形细胞肉瘤,发生于腹腔内还可被误认为胃肠道间质瘤,给患者带来不必要的过度治疗.本文报道1例误诊的胃壁富于细胞性神经鞘瘤,分析该病的临床特点、诊断及治疗.     

溶瘤病毒与泌尿系统肿瘤

溶瘤病毒是一类具有复制能力的肿瘤杀伤型病毒,溶瘤病毒治疗肿瘤是新兴的肿瘤基因治疗途径.溶瘤病毒可以通过复制,增殖,最后裂解杀死肿瘤细胞,因此成为近年来的研究热点之一.本文就溶瘤病毒研究发展史、分类、作用机制及其在泌尿系统常见肿瘤治疗中的研究进展作一综述.     

溶瘤腺病毒的临床应用进展

溶瘤腺病毒,也称为条件复制性腺病毒(conditionally replicating adenovirus,CRAd),具有在肿瘤特异性增殖,而在正常细胞中不能进行增殖的特性.溶瘤腺病毒最近几年得到迅猛发展,目前已有溶瘤腺病毒的生物制剂应用到临床中,此外还有很多种溶瘤腺病毒处于临床试验中,应用前景广阔.本文就溶瘤腺病毒在临床的应用作一综述.     

腹膜假性黏液瘤的临床综合诊治现状

腹膜假性黏液瘤(pseudomyxoma peritonei,PMP)是一种以黏液外分泌性细胞为主,在腹膜或网膜种植导致腹腔内大量胶冻状黏液性腹水为特征的疾病,临床上无特异治疗方法,预后不佳~([1]).腹腔热灌注化疗(IHPC)作为一种新兴的治疗手段,在预防与治疗腹腔恶性肿瘤的腹腔内种植性转移及其并发的恶性腹水方面有独到优势.现将肿瘤细胞减瘤术(CRS)后应用IHPC治疗PMP的临床应用现状作一简要综述.     

恶性腹膜间皮瘤治疗方案研究进展

恶性腹膜间皮瘤是临床罕见的恶性肿瘤, 因其发病隐匿且缺乏特异性表现, 治疗手段匮乏, 仅有少部分人群可以接受手术治疗。随着肿瘤细胞减灭术联合腹腔热灌注化疗的不断发展, 在一定程度上改善了患者的预后。同时, 大量的靶向治疗和免疫治疗相关临床试验也为腹膜间皮瘤患者提供了治疗思路, 增加了全身治疗方案的可选择性。本文拟对恶性腹膜间皮瘤的治疗方案和研究进展作一综述。     

巨大精囊孤立性纤维性肿瘤1例报道

孤立性纤维性肿瘤(solitary fibrous tumor,SFT)长期以来被认为系间皮起源,是间皮瘤的一个类型,称为纤维性间皮瘤.但随着现代技术的发展,现在认为SFT属于一种间叶源性肿瘤,本文报道1例临床十分罕见的精囊SFT.     

腹膜良性多囊性间皮瘤合并慢性阑尾炎1例及文献复习

腹膜良性多囊性间皮瘤是一种罕见良性肿瘤，对于该病的了解多通过个案报道。本文报道了1例腹膜良性多囊性间皮瘤合并慢性阑尾炎的患者，手术治疗后随访20个月无复发，并结合患者的临床资料及文献进行了讨论。     

Current status of clinical trials assessing oncolytic virus therapy for urological cancers

Oncolytic virus therapy has recently been recognized as a promising new option for cancer treatment. Oncolytic viruses replicate selectively in cancer cells, thus killing them without harming normal cells. Notably, T‐VEC (talimogene laherparepvec, formerly called OncoVEX^GM‐CSF), an oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in October 2015, and was subsequently approved in Europe and Australia in 2016. The efficacies of many types of oncolytic viruses against urological cancers have been investigated in preclinical studies during the past decade, and some have already been tested in clinical trials. For example, a phase I trial of the third‐generation oncolytic Herpes simplex virus type 1, G47Δ, in patients with prostate cancer was completed in 2016. We summarize the current status of clinical trials of oncolytic virus therapy in patients with the three major urological cancers: prostate, bladder and renal cell cancers. In addition to Herpes simplex virus type 1, adenoviruses, reoviruses, vaccinia virus, Sendai virus and Newcastle disease virus have also been used as parental viruses in these trials. We believe that oncolytic virus therapy is likely to become an important and major treatment option for urological cancers in the near future.     

Viral Oncolysis for Malignant Liver Tumors

Viral oncolysis represents a unique strategy to exploit the natural process of viral replication to kill tumor cells. Although this concept dates back nearly a century, recent advances in the fields of molecular biology and virology have enabled investigators to genetically engineer viruses with greater potency and tumor specificity. In this article we review the general mechanisms by which oncolytic viruses achieve their antineoplastic efficacy and specificity. We focus on the development of several classes of oncolytic viruses for the treatment of malignant liver tumors, including adenoviruses, vaccinia viruses, and herpes simplex viruses, and discuss the results of clinical trials for these viruses. We also describe results from our laboratory research program, which is focused on developing effective, liver tumor–specific Herpes simplex virus 1 mutants.     

Employing Tumor Hypoxia for Oncolytic Therapy in Breast Cancer

Hypoxia is a common tumor condition associated with metastases, therapeutic resistance, and poor patient survival. Forty percent of breast cancers are hypoxic, with a median oxygen concentration of 3.9%, and a third of tumors have regions less than 0.3%. Normal breast tissue is reported to have oxygen concentrations greater than 9%. This tumor hypoxia in breast cancer confers resistance to conventional radiation therapy and chemotherapy, as well as making estrogen-receptor-positive tumors less sensitive to hormonal therapy. Novel treatment modalities are needed to target hypoxic tumor cells. Lower tumor oxygen levels compared with surrounding normal tissues may be utilized to target and enhance herpes oncolytic viral therapy in breast cancer. Attenuated oncolytic herpes simplex viruses offer a unique cancer treatment by specifically infecting, replicating within, and lysing tumor cells. They carry genetically engineered mutations to reduce their virulence and attenuate their ability to infect normal tissues. Studies have shown the safety and efficacy of oncolytic herpes simplex viruses in treating breast cancer both in humans and in preclinical models. The placement of essential viral genes under the control of a hypoxia-responsive enhancer, which is upregulated selectively in hypoxic tissue, represents a promising strategy to target oncolytic viruses precisely to hypoxic cancer cells. In this review we describe strategies to harness hypoxia as a trigger for oncolytic viral gene expression in breast cancer, thereby increasing the specificity of viral infection, replication, and cytotoxicity to hypoxic areas of tumor. Such a targeted approach will increase efficacy in the therapy of hypoxic tumors while achieving a reduction in total dose of viral therapy.Supported in part by AACR-Astra Zeneca Cancer Research and Prevention Foundation Fellowship (P.S.A), grants RO1 CA 75416 and RO1 CA/DK80982 (Y.F.) from the National Institutes of Health, grant MBC-99366 (Y.F.) from the American Cancer Society, grant BC024118 from the US Army (Y.F.), grant IMG0402501 from the Susan G. Komen Breast Cancer Foundation (Y.F. and P.S.A.) and grant 032047 from Flight Attendant Medical Research Institute (Y.F. and P.S.A.)     

Oncolytic herpes viral therapy is effective in the treatment of hepatocellular carcinoma cell lines

The rising incidence of hepatocellular carcinoma (HCC) in western countries, along with the poor prognosis offered by present-day treatment modalities, makes novel therapies for this disease necessary. Oncolytic herpes simplex viruses (HSV) are replication-competent viruses that are highly effective in the treatment of a wide variety of experimental models of human malignancies. This study seeks to investigate the effectiveness of oncolytic herpes viruses in the treatment of primary HCC cell lines. Sixteen commercially available human HCC cell lines were studied. G207 is an attenuated, replication-competent, oncolytic HSV engineered to selectively replicate within cancer cells. Cell lines were tested for viral sensitivity to G207 and their ability to support viral replication using standard cytotoxicity and viral replication assays. Eleven of 16 cell lines were moderately to highly sensitive to G207 viral oncolysis. HCC cell lines additionally demonstrated the ability to support viral replication in vitro with as high as 800-fold amplification of the administered viral dose observed. G207 is cytotoxic to, and efficiently replicates within, HCC cell lines in vitro. From these data, we suggest that oncolytic HSV therapy may have a role in the treatment of HCC, and in vivo studies are warranted. Presented in part at the 2005 American Hepato-Pancreato-Biliary Association Congress, Hollywood, Florida, April 14–17, 2005. Supported by grants R01CA75461 and R01CA72632 from the National Institutes of Health, and by grant MBC-99366 from the American Cancer Society (Yuman Fong).     

Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for treatment of colorectal and hepatic adenocarcinomas

BACKGROUND: Oncolytic cancer therapy using herpes simplex viruses (HSV) that have direct tumoricidal effects and cancer immunotherapy using the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have each been effective in preclinical testing. NV1034 is a multimutated oncolytic HSV carrying the gene for murine GM-CSF that attempts to combine these 2 anticancer strategies. The purpose of this study was to compare NV1034 to NV1023, the parent HSV mutants lacking GM-CSF, to determine if such combined oncolytic and immunotherapy using a single vector has advantages over oncolytic therapy alone. METHODS: Expression GM-CSF in vitro did not alter the infectivity, cytotoxicity, or replication of NV1034 compared to the noncytokine-secreting control. Tumors infected with NV1034 produced GM-CSF in picogram quantities. In vivo efficacy of the viruses against murine colorectal carcinoma CT26 and murine hepatoma Hepa l-6 was then tested in subcutaneous tumors in syngeneic Balb/c and C57 L/J mice, respectively. In these immune-competent models, NV1034 and NV1023 each demonstrated potent antitumor activity. RESULTS: Treatment with NV1034 had significantly better antitumor effect compared to treatment with NV1023. Furthermore, there was no difference in the antitumor efficacy of these viruses in mice depleted of CD4+ and CD8+ T lymphocytes. CONCLUSIONS: Viral vectors combining oncolytic and immunotherapy are promising agents in treatment of colorectal carcinoma and hepatoma.     

Oncolytic virus therapy for prostate cancer

The use of replication-competent viruses that can selectively replicate in and destroy neoplastic cells is an attractive strategy for treating cancer. Various oncolytic viruses have been taken to clinical trials since a recombinant virus was first applied to cancer patients a decade ago. The concept of the therapy is simple: infectious virus kills the host cancer cells in the course of viral replication. It is important, however, that the virus does not harm the surrounding normal tissue. Oncolytic viruses can be classified largely into two groups: DNA viruses genetically engineered to achieve cancer specificity (e.g. adenovirus, herpes simplex virus and vaccinia) and RNA viruses of which human is not the natural host (e.g. Newcastle disease virus and reovirus). Prostate cancer has always been one of the major targets of oncolytic virus therapy development. The result of six clinical trials for prostate cancer has been published and several trials are now going on. Forty-eight of 83 (58%) patients evaluated in the phase I studies demonstrated a >25% decrease in serum prostate-specific antigen level without evidence of severe toxicities. The result shows the oncolytic virus therapy is promising toward clinical application. Here, we review the recent advances in the field and summarize the results from clinical trials.     

Potent antitumor activity after systemic delivery of a doubly fusogenic oncolytic herpes simplex virus against metastatic prostate cancer

BACKGROUND: Although conventional radiation therapy and surgery are potentially curative treatments for organ-confined prostate cancer, there are few effective treatments for metastatic disease. Oncolytic viruses have shown considerable promise for the treatment of solid tumors including prostate cancer. We recently demonstrated that incorporation of a cell membrane fusion capability into an oncolytic herpes simplex virus (HSV) can significantly increase the antitumor potency of the virus. METHODS: We used a mouse model of primary and metastatic human prostate cancer established from PC-3M-Pro4 to evaluate three different types of oncolytic HSVs: non-fusogenic Baco-1, singly fusogenic Synco-2, and doubly fusogenic Synco-2D. RESULTS: Our results show that Synco-2D has greater oncolytic activity than either Baco-1 or Synco-2 virus. Against lung metastases of human prostate cancer xenografts, intravenous administration of Synco-2D had produced a significant reduction of tumor nodules by day 40 post-inoculation as compared with Synco-2 (P < 0.05), Baco-1 (P < 0.01), and PBS control (P < 0.01). CONCLUSIONS: We conclude that the doubly fusogenic Synco-2D is an effective therapeutic agent for human metastatic prostate cancer.     

YB-1-basierte Virotherapie

Therapeutic intervention using oncolytic viruses is called virotherapy. This type of virus is defined by the ability to replicate in tumor cells only and to destroy these cells upon replication. In addition, this virus type is able to induce a tumor-directed immune response. Early clinical trials have confirmed the safety profile of oncolytic viruses. Currently, different groups are working on the development of oncolytic viruses with a focus on treatment of nonmuscle invasive bladder cancer (NMIBC). A preliminary active recruiting clinical phase II/III trial ongoing in patients with a NMIBC was recently implemented in the United States. Our research group developed an oncolytic adenovirus that will soon enter a clinical phase I trial in patients diagnosed with glioma. This virus is being further modified for the treatment of NMIBC. In this review article, recent developments in the design and use of virotherapy in bladder cancer are summarized.     

Treatment of solid sarcomas in immunocompetent mice with novel, oncolytic herpes simplex viruses.

OBJECTIVE: Attenuated, replication-competent herpes simplex viruses (HSVs) have shown promise as antitumor agents for cancer therapy. In this study, we sought to develop a novel type of oncolytic HSV with more potent antitumor activity for use in localized malignant tumors. STUDY DESIGN: A new, attenuated multimutated HSV (termed HL) was developed, and then a highly metastatic murine fibrosarcoma cell line, NfSa Y83, was injected into the necks or flanks of immunocompetent C3H mice. The mice were treated with attenuated HSV mutants by intratumoral injection, and antitumor efficacy was assessed by measuring tumor dimensions and overall survival rates. RESULTS: Treatment with intratumoral injection of HL resulted in marked regression of tumors. In fact, roughly 75% of flank tumors and 50% of neck tumors were completely eradicated. CONCLUSION: A novel type of attenuated HSV recombinant HL demonstrated a remarkable antitumor efficacy in a localized tumor model in mice.