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溶瘤病毒

溶瘤病毒（英語：oncolytic virus）是一种优先(preferentially)侵染并溶解癌细胞的病毒；these have obvious functions for cancer therapy, both by direct destruction of the 肿瘤 cells, and, if modified, as vectors enabling genes expressing anticancer proteins to be delivered specifically to the tumor site.

Most current oncolytic viruses are engineered for tumour selectivity, though there are a few naturally occurring ones such as the Seneca Valley virus.

历史[编辑]

癌症和病毒之间的联系has long been theorized, and case reports of cancer regression (cervical cancer, Burkitt lymphoma, Hodgkin lymphoma) after immunization or infection with an unrelated virus appeared at the beginning of the 20th century.[1] Efforts to treat cancer through immunization or deliberate infection with a virus began in the mid 20th century.[1][2] As the technology for creating a custom virus did not exist, all early efforts focused on finding natural oncolytic viruses. During the 1960s, promising research involved in using poliovirus,[3] adenovirus,[1] Coxsackie virus,[4] and others.[2] The early complications were occasional cases of uncontrolled infection, resulting in significant morbidity and mortality; the very frequent development of an immune response, while harmless to the patient,[1] destroyed the virus and thus prevented it from destroying the cancer.[3] Only certain cancers could be treated through virotherapy was also recognized very early.[4] Even when a response was seen, these responses were neither complete nor durable.[1] The field of virotherapy was nearly abandoned for a time.[1]

随着先进基因工程技术的later发展，研究者们能够to deliberately modify existing viruses, or to create new ones. All modern research on 溶瘤病毒 involves viruses that have been modified to be less susceptible to immune suppression, to more specifically target particular classes of cancer cells, or to express desired cancer-suppressing genes.

H101病毒[编辑]

第一种 to be approved by a regulatory agency的溶瘤病毒是一种被上海三维生物技术有限公司(Shanghai Sunway Biotech Co. Ltd.)命名为H101病毒的转基因腺病毒(adenovirus)。 It gained regulatory approval in 2005年 from 国家食品药品监督管理局(SFDA) for the treatment of head and neck cancer.[5][6] Sunway's H101 and the very similar Onyx-15 have been engineered to remove a viral defense mechanism that interacts with a normal human gene p53, which is very frequently dysregulated in cancer cells.[6] Despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially.[6] While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone.[6] It appears to works best when injected directly into a tumor, and when any resulting fever is not suppressed.[6] Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease.[7]

可能的应用[编辑]

病毒基因治疗 has never been used successfully against cancer, mainly due to poor transduction of cells. This problem is solved by oncolytic viruses. The use of viral agents to treat cancer is now a real possibility, and several very promising advances have been made, e.g. ONYX-015 and MV-ERV. The most advanced oncolytic virus, based on herpes simplex is OncoVEX GM-CSF which is in 第三期临床试验 in 黑素瘤和头颈癌.[8] This virus has given a 20% complete response rate in melanoma, a level of efficacy which has never been seen by any agent in melanoma before.[來源請求]

Viral agents administered intravenously can be particularly effective against metastatic cancers, which are especially difficult to treat conventionally. However, blood-borne viruses can be deactivated by 抗体 and cleared from the blood stream quickly e.g. by Kupffer cells (extremely active phagocytic cells in the liver, which are responsible for adenovirus clearance). Avoidance of the immune system until the tumour is destroyed could be the biggest obstacle to the success of oncolytic virus therapy. To date, no technique used to evade the immune system is entirely satisfactory.[來源請求] It is in conjunction with conventional cancer therapies that oncolytic viruses have often showed the most promise, since combined therapies operate synergistically with no apparent negative effects.[來源請求] An exception to each of these points is again provided by OncoVEX GM-CSF (BioVex Inc, Woburn MA), the efficacy of which has been found not to be compromised by host immunity, and with which stand alone therapy has provided an approximately 30% response rate (PR + CR) against systemic disease, following local injection into accessible tumors. This is because this virus stimulates a systemic anti-tumor immune response enhanced through the expression of GM-CSF in the dying tumor micro-environment.[來源請求] OncoVEX GM-CSF is currently completing a pivotal Phase 3 trial in melanoma, the first pivotal trial with an oncolytic virus to ever be conducted, and a phase 3 trial in head and neck cancer is also underway.[8][9] (The developer of OncoVEX GM-CSF, BioVex Inc, was purchased by Amgen for $1 billion in January 2011.)

The specificity and flexibility of oncolytic viruses means they have the potential to treat a wide range of cancers with minimal side effects. However, altering the host range or tissue specificity of any virus has significant safety implications.

临床研究[编辑]

  • OncoVEX GM-CSF (see above) developed by BioVex is currently in phase III for advanced 黑素瘤, and likely to become the first approved oncolytic agent in the 西方世界.[來源請求] OncoVEX GM-CSF is also currently being tested in a pivotal phase 3 trial in head and neck cancer.
  • REOLYSIN, in phase III for Head and neck cancer.[8] Encouraging early results in colorectal cancer.[10]
  • CGTG-102 (Ad5/3-D24-GMCSF) by Oncos Therapeutics, while in phase I already used to treat 200 advanced cancer patients in company's Advanced Therapy Access Program.[17]

Non-oncolytic viral therapy :

Oncolytic viruses in conjunction with existing cancer therapies[编辑]

Chen et al. (2001)[25] used CV706, a prostate-specific adenovirus, in conjunction with radiotherapy on prostate cancer in mice. The combined treatment resulted in a synergistic increase in cell death, as well as a significant increase in viral burst size (the number of virus particles released from each cell lysis). No alteration in viral specificity was observed.

ONYX-015 has undergone trials in conjunction with chemotherapy. The combined treatment gave a greater response than either treatment alone, but the results have not been entirely conclusive. ONYX-015 has shown promise in conjunction with radiotherapy.[來源請求] Abandoned in 2000.

Engineering oncolytic viruses[编辑]

Selection criteria[编辑]

The virus should be able to tolerate storage and production at high titres. A double-stranded DNA genome is advantageous because it has greater stability during storage, which reduces the chances of hazardous mutations. Viruses like adenoviruses and herpes simplex virus are the most[來源請求] suitable, and have been the most extensively studied.

Generating tumour selectivity[编辑]

There are two main approaches for generating tumour selectivity: transductional and non-transductional targeting. Transductional targeting involves modifying the specificity of viral coat protein, thus increasing entry into target cells while reducing entry to non-target cells. Non-transductional targeting involves altering the genome of the virus so it can only replicate in cancer cells. This can be done by either 转录 targeting, where 基因 essential for 病毒的DNA复制 are placed under the control of 一种肿瘤特异性启动子, or by 减毒(attenuation), which involves introducing deletions into the viral genome that eliminate functions that are dispensable in cancer cells, but not in normal cells. There are also other, slightly more obscure methods.

Transductional targeting[编辑]

This approach to tumour selectivity has mainly focused on adenoviruses, although it is entirely viable with other viruses. However, it should be recognised that increasing the host tissue range of a virus has serious safety implications.

The most commonly used group of adenoviruses is 血清型 5 (Ad5), whose binding to 宿主细胞 is initiated by interactions between the cellular coxsackievirus and adenovirus receptor (CAR), and the knob domain of the adenovirus coat protein trimer. Li et al. (1999)[26] showed that CAR is necessary for adenovirus infection by showing that CAR-negative cells could be made adenovirus-sensitive by transfection with CAR cDNA. Virus internalisation depends on an Arginine-Glycine-Asparagine (RGD) motif at the base of adenovirus coat protein that binds to integrins, causing endocytosis. It has been suggested that CAR has a role in cell adhesion, and possibly tumour suppression. Although expressed widely in epithelial cells, CAR expression in tumours is extremely variable, leading to resistance to Ad5 infection. Retargeting of Ad5 from CAR, to another receptor that is ubiquitously expressed on cancer cells, enables reduction of Ad5 tropism, enhancing infection of CAR deficient target cells. This can be done in one of two ways:

Adapter molecules[编辑]

Bi-specific adapter molecules can be administered along with the virus to redirect viral coat protein tropism. These molecules are fusion proteins that are made up of an antibody raised against the knob domain of the adenovirus coat protein, fused to a natural ligand for a cell-surface receptor. The use of adapter molecules has been shown to increase viral transduction. However, adapters add complexity to the system, and the effect of adapter molecule binding on the stability of the virus is uncertain.

Coat-protein modification[编辑]

This method involves genetically modifying the fiber knob domain of the viral coat protein to alter its specificity. Wickham et al. (2003)[27] added short peptides to the C-terminal end of the coat protein, which successfully altered viral tropism. The addition of larger peptides to the C-terminus is not viable because it reduces adenovirus integrity, possibly due to an effect on fiber trimerisation. The fiber protein also contains an HI-loop structure, which can tolerate peptide insertions of up to 100 residues without any negative effects on adenovirus integrity. Davydova et al. (2004)[28] inserted an RGD motif in the HI loop of the fiber knob protein, shifting specificity toward integrins, which are frequently over-expressed in Oesophageal Adenocarcinoma. When combined with a form of non-transductional targeting, these viruses proved to be effective and selective therapeutic agents for Oesophageal Adenocarcinoma.

Non-transductional targeting[编辑]

Transcriptional targeting[编辑]

Transcriptional targeting places an essential viral gene under the control of a tumour-specific promoter, meaning the gene is only expressed in cell types where all the transcription factors required for promoter function are active. A suitable promoter should be active in the tumour but inactive in the majority of normal tissue, particularly the liver, which is the organ that is most exposed to blood born viruses. Many such promoters have been identified and studied for the treatment of a range of cancers.

Cyclooxygenase-2酶 (Cox-2) expression is elevated in a range of cancers, and has low liver expression, making it a suitable tumour-specific promoter. Davydova et al. (2004)[28] targeted AdCox2Lluc, a conditionally replicating adenovirus (CRAd), against Oesophageal Adenocarcinoma by placing the early genes under the control of a Cox-2 promoter (adenoviruses have two early genes, E1A and E1B, that are essential for replication). When combined with transductional targeting, AdCox2Lluc showed potential for treatment of Oesophageal Adenocarcinoma. Cox-2 is also a possible tumour-specific promoter candidate for other cancer types, including ovarian cancer.

一种合适的前列腺癌肿瘤特异性启动子是前列腺特异抗原(PSA), PSA的表达 is greatly elevated in prostate cancer. CN706 is a CRAd with a PSA tumour-specific promoter driving expression of the adenoviral E1A gene, required for viral replication. Rodriguez et al. (1997)[29] showed that the CN706 titre is significantly greater in PSA-positive cells.

Attenuation[编辑]

癌细胞和受病毒侵染的细胞有着相似的alterations in their cell signalling pathways, particularly those that govern progression through the cell cycle. A viral gene whose function is to alter a pathway is dispensable in cells where the pathway is defective, but not in cells where the pathway is active. Attenuation involves deleting viral genes, or gene regions, to eliminate viral functions that are expendable in tumour cell, but not in normal cells.

For adenovirus replication to occur, the host cell must be induced into S-phase by viral proteins interfering with cell cycle proteins. The adenoviral E1A gene is responsible for inactivation of several proteins, including Retinoblastoma, allowing entry into S-phase. The adenovirus E1B55kDa gene cooperates with another adenoviral product, E4ORF6, to inactivate p53, thus preventing apoptosis. It was initially proposed that an Adenovirus mutant lacking the E1B55kDa gene, dl1520 (ONYX-015), could replicate selectively in p53 deficient cells. ONYX-015 was subsequently elevated into clinical trials in patients with advanced head and neck cancer, however the outcomes were marginal. ONYX-015 when combined with chemotherapy, however, proved reasonably effective in a proportion of cases. During these trials a plethora of reports emerged challenging the underlying p53-selectivity, with some reports showing that in some cancers with a wild-type p53 ONYX-015 actually did better than in their mutant p53 counterparts. These reports slowed the advancement through Phase III trials in the US, however recently China licensed ONYX-015 for therapeutin use as H101.[30] Outside of China, the push to the clinic for ONYX-015 has been largely been discontinued for financial reasons and until a real mechanism can be found.[31]

Carette et al. (2004)[32] used Ad5- Δ24E3, a CRAd with a 24 base pair deletion in the retinoblastoma-binding domain of the E1A protein, making it unable to silence retinoblastoma, and therefore unable to induce S-phase in host cells. This means Ad5-Δ24E3 is only able to replicate in proliferating cells, such as tumour cells. The adenovirus was used to deliver short hairpin RNA, which was able to reduce expression of the luciferase target gene in target cells to 30%, relative to the control, by RNA interference.

The herpes simplex virus genome contains the enzymes thymidine kinase and ribonucleotide reductase, whose cellular forms are responsible for the production of dNTP’s required for DNA synthesis and are only expressed during the G1 and S phases of the cell cycle. These enzymes allow herpes simplex virus replication in quiescent cells, so if they are inactivated by mutation the herpes simplex virus will only be able to replicate in proliferating cells, such as cancer cells. The G207 herpes simplex virus mutant contains a LacZ insertion, inactivating ribonucleotide reductase, as well as deletion of a virulence gene for safety's sake, has progressed to clinical trials for the treatment in brain cancer.[來源請求]

Double targeting[编辑]

It is unlikely to be possible to make a virus entirely specific toward any tissue type by using just one form of targeting. Infection of normal tissue can result in adverse side effects. Double targeting with both transductional and non-transductional targeting methods is more effective than any one form of targeting alone. Davydova et al. (2004) combined transductional targeting with a tumour-specific promoter to successfully target an adenovirus against Oesophageal Adenocarcinoma.[來源請求]

Modifications to improve oncolytic activity[编辑]

自杀基因[编辑]

Viruses can be used as vectors for delivery of suicide genes, encoding enzymes that can metabolise a separately administered non-toxic pro-drug into a potent 细胞毒素, which can diffuse to and kill neighbouring cells. One herpes simplex virus, encoding a thymidine kinase suicide gene, has progressed to phase III clinical trials. The herpes simplex virus thymidine kinase phosphorylates the pro-drug, ganciclovir, which is then incorporated into DNA, blocking DNA synthesis. The tumour selectivity of oncolytic viruses ensures that the suicide genes are only expressed in cancer cells.[來源請求]

抑制血管生成[编辑]

血管生成(angiogenesis) is an essential part of the formation of large tumour masses. Angiogenesis can be inhibited by the expression of several genes, which can be delivered to cancer cells in viral vectors, resulting in suppression of angiogenesis, and oxygen starvation in the tumour. The infection of cells with viruses containing the genes for angiostatin and endostatin synthesis inhibited tumour growth in mice. Enhanced antitumor activities have been demonstrated in a recombinant vaccinia virus encoding anti-angiogenic therapeutic antibody.[33]

免疫应答[编辑]

In a number of cases, cancer cells exposed to viruses have experienced widespread necrosis, which cannot be entirely accounted for by viral replication alone. Cytotoxic T-cell responses directed against virus-infected cells have been identified as an important factor in tumour necrosis.[來源請求]

However, since viruses are normal human pathogens, they induce an immune response, which reduces their effectiveness. Increased antibody titers could deactivate viruses before the tumour has been destroyed. This can be partly overcome by using parental viruses that are not normal human pathogens, thereby avoiding any pre-existing immunity. However, this does not avoid subsequent antibody generation. Alternatively, the viral vector can be coated with a polymer such as polyethylene glycol, shielding it from antibodies, but this also prevents viral coat proteins adhering to host cells.[來源請求] Deactivation of the immune system is not desirable, since it has a positive effect on tumour necrosis.[來源請求]

Oncolytic behaviour of wild-type viruses[编辑]

水泡性口膜炎病毒[编辑]

水泡性口膜炎病毒(vesicular stomatitis virus, VSV) is a rhabdovirus, consisting of 5 genes encoded by a negative sense, single-stranded RNA genome. In nature, VSV infects insects as well as livestock, where it causes a relatively localized and non-fatal illness. The low pathogenicity of this virus is due in large part to its sensitivity to interferons, a class of proteins that are released into the tissues and bloodstream during infection. These molecules activate genetic anti-viral defence programs that protect cells from infection and prevent spread of the virus. However in 2000, Stojdl and Lichty et al.[34] demonstrated that defects in these pathways render cancer cells unresponsive to the protective effects of interferons and therefore highly sensitive to infection with VSV. Since VSV undergoes a rapid cytolytic replication cycle, infection leads to death of the malignant cell and roughly a 1000-fold amplification of virus within 24h. VSV is therefore highly suitable for therapeutic application, and several groups (Stojdl et al., 2003,[35] Ahmed et al., 2004,[36] Ebert et al. 2005[37] and Porosnicu et al., 2003[38] have gone on to show that systemically administered VSV can be delivered to a tumor site, where it replicates and induces disease regression, often leading to durable cures. Attenuation of the virus by engineering a deletion of Met-51 of the matrix protein ablates virtually all infection of normal tissues, while replication in tumor cells is unaffected (Stojdl et al., 2003).[35]

Recent research has shown that this virus has the potential to cure brain tumors, thanks to its oncolytic properties.[來源請求]

脊髓灰质炎病毒[编辑]

脊髓灰质炎病毒(Poliovirus) is a natural neuropathogen, making it the obvious choice for selective replication in tumours derived from neuronal cells. 脊髓灰质炎病毒的基因组是单正链RNA, 其翻译依赖于一种组织特异性internal ribosomal entry site (IRES) within the 5' untranslated region of the 病毒基因组, which is active in cells of neuronal origin and allows translation of the viral genome without a 5’ cap. Gromeier et al. (2000)[39] replaced the normal poliovirus IRES with a rhinovirus IRES, altering tissue specificity. The resulting PV1(RIPO) virus was able to selectively destroy malignant glioma cells, while leaving normal neuronal cells untouched.[來源請求]

呼肠孤病毒[编辑]

呼吸道肠道孤儿病毒（Respiratory Enteric Orphan virus, 首字母缩写为Reovirus）, generally infects mammalian respiratory and bowel systems. Most people have been exposed to reovirus by adulthood; however, the infection does not typically produce symptoms. The link to the reovirus’ oncolytic ability was established after it was discovered to reproduce well in various cancer cell lines and lyses these cells.[40]

Reolysin is a formulation of reovirus that is currently in clinical trials for the treatment of various cancers.[41]

In fiction[编辑]

在科学幻想, the concept of an oncolytic virus was first introduced to the public in Jack Williamson's novel Dragon's Island, published in 1951, although Williamson's imaginary virus was based on a bacteriophage rather than a mammalian virus. 《龙之岛》(Dragon's Island) 也因作为“基因工程”这一术语的出处而闻名。[來源請求]

好莱坞电影《我是传奇》(I Am Legend) is based on the premise that 一种癌症病毒疗法造成了一种全球性流行病。This fictional tale emphasizes a major concern with oncolytic viruses: that mutations could possibly destroy the host.[來源請求]

参考文献[编辑]

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