Adenovirus varieties have been widely explored as viral vectors for gene therapy and also as oncolytic virus.
Of the many types of viruses explored for oncolytic potential, adenovirus is the first approved by regulatory bodies, genetically modified H101 strains. It obtained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer.
Video Oncolytic adenovirus
Rekayasa oncolytic adenovirus
Adenovirus has so far gone through three generations of development. Some strategies for adenovirus modification are described below.
Attenuation
For adenovirus replication to occur, host cells should be induced into phase S by viral proteins that interfere with cell cycle proteins. The adenoviral E1A gene is responsible for disabling some proteins, including retinoblastoma, which allows entry into the S-phase. The adenovirus E1B55kDa gene works in conjunction with another adenoviral product, E4ORF6, to disable p53, thereby preventing apoptosis. Initially it was proposed that adenovirus mutants lacking the E1B55kDa gene, dl1520 (ONYX-015), may replicate selectively in p53 deficiency cells.
Replicative conditional adenovirus (CRAd) with deletion of 24 base pairs in the binding domain of E1A protein retinoblastoma ( Ad5-? 24E3 ), is unable to silence retinoblastoma, and therefore can not induce S-phase in host cell. This limits Ad5-? 24E3 for replication only in cells proliferating, such as tumor cells.
Targeting
The most commonly used adenovirus group is serotype 5 (Ad5), which binds to its host cell initiated by the interaction between coxsackie cellular virus and adenovirus receptor (CAR), and the knob domain of adenovirus coat protein trimer. CAR is required for adenovirus infection. Although widely expressed in epithelial cells, CAR expression in tumors varies widely, leading to resistance to Ad5 infections. Ad5 targeting of CAR, to other receptors commonly expressed in cancer cells, can overcome this resistance.
- Adapter molecules
- Bi-specific adapter molecules can be administered along with viruses to divert the tropism of the virus causing virus. These molecules are fusion proteins made from antibodies that are elevated against the adenovirus coat protein key domain, blending with the natural ligand for cell surface receptors. The use of adapter molecules has been shown to increase viral transduction. However, the adapter adds to the complexity of the system, and the adapter molecular effects that bind to the stability of the virus are uncertain.
- coat-protein modification
- This method involves genetically modifying the protein knob domain of the viral protein layer to change its specificity. Short peptides added to the terminals of the C-terminals of the mantle proteins successfully alter the viral tropism. The addition of larger peptides to C-terminus is not feasible because it reduces adenovirus integrity, possibly because of the effects on fiber trimerization. The fiber protein also contains a HI loop structure, which can tolerate peptide insertion of up to 100 residues without negative effects on adenovirus integrity. RGD motifs are fed into the HI loop of the knob fiber protein, shifting the specificity to integrins, which are often overexpressed in adenocarcinoma of the esophagus. When combined with non-transductional targeting forms, the virus proves to be an effective and selective therapeutic agent for Adenocarcinoma Oesophageal.
- Transcript targeting
- This approach takes advantage of a deregulated promoter to control and control adenoviral gene expression. For example, the expression of the Cyclooxygenase-2 enzyme (Cox-2) increases in various types of cancer, and has a low liver expression, making it a tumor-specific promoter accordingly. AdCox2Lluc is CRAdarget against adenocarcinoma of the esophagus by placing the initial gene under the control of Cox-2 promoter (adenovirus has two early genes, E1A and E1B, which are important for replication). When combined with transductional targeting, AdCox2Lluc demonstrates the potential for treatment of Oesophageal Adenocarcinoma. Cox-2 is also likely a tumor-specific promoter candidate for other types of cancer, including ovarian cancer.
- A tumor-specific promoter suitable for prostate cancer is a prostate-specific antigen (PSA), whose expression is greatly increased in prostate cancer. CN706 is CRAd with expression driving specific promoter of PSA tumor from adenovirus E1A gene, which is required for viral replication. The CN706 titer was significantly greater in PSA-positive cells.
- Post-Transcription Targeting
- Another regulatory layer that appears to control adenoviral replication is the use of artificial target sites for microRNAs (miRNA) or miRNA response elements (MREs). The difference in miRNA expression between healthy tissue and tumor allows to engineer the oncolytic virus in order to have the ability to replicate disruption in attractive tissues while allowing its replication in tumor cells.
Maps Oncolytic adenovirus
Example
Oncorine (H101)H101 and Onyx-015 are very similarly engineered to remove the viral defense mechanisms that interact with the normal human gene p53 , which is very often dysregulated in cancer cells. In spite of early laboratory labor promises in vivo, these viruses do not specifically infect cancer cells, but they still kill cancer cells in a special way. While the overall survival rate is unknown, short-term response rates are approximately double for H101 plus chemotherapy when compared with chemotherapy alone. It seems to work best when injected directly into the tumor, and when the resulting fever is not suppressed. Systemic therapy (such as by intravenous line infusion) is desirable to treat metastatic disease. Now marketed under the brand name Oncorine .
Onyx-015 ( dl 1520)
Onyx-015 (originally named Ad2/5 dl1520) is an experimental oncolytic virus made by genetically engineered adenovirus. It has been tested as a possible treatment for cancer. The E1B-55kDa gene has been removed allowing the virus to selectively replicate and lyse p53-deficient cancer cells.
Director of Evolution
Traditional research has focused on the Adenovirus serotype 5 (Ad5) C species to create an oncolytic vaccine for potential use as a cancer treatment. However, recent data suggest that it may not be the best viral serotype to degrade all oncolytic agents to treat human malignancies. For example, the oncolytic vaccine based on Ad5 serotype has relatively poor clinical efficacy as monotherapy. The need for increased potential (infectivity and lytic activity) has led to an expanded search involving a large number of poorly studied adenovirus serotypes.
ColoAd1
One non-species of C oncolytic adenovirus currently under development is ColoAd1. It was created using a process of "directed evolution". This involves the creation of new viral variants or serotypes that are specifically directed against tumor cells through a selection cycle directed using large populations of recombinant recombinant precursor viruses. The increased biodiversity generated by the initial homologous recombination step provides a large random collection of viral candidates which can then be passed through a series of selection steps designed to lead to predetermined results (eg higher tumor specific activity) without the need for prior knowledge. the resulting viral mechanism that is responsible for that outcome. One specific application of this approach produces ColoAd1, which is a new oncolytic virus from Ad11p/Ad3 chimeric B with a specificity for colon cancer and a broad spectrum of anti-cancer activity in common solid tumors. The efficacy of ColoAd1 therapy is currently being evaluated in three ongoing clinical trials (see EU Clinical Test List for more details). Potential ColoAd1 can be further enhanced through the use of transgenes therapy, which can be introduced into the ColoAd1 genome without sacrificing selectivity or viral activity. Recent studies with ColoAd1 have demonstrated a unique cell death mechanism similar to Oncosis with expression markers of inflammatory cell death and blistered cell membranes.
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Tumors are formed in cells when mutations in the genes involved in cell cycle control and apoptosis accumulate over time. Most of the tumors were studied, having a defect in the p53 tumor suppressor pathway. p53 is a transcription factor that plays a role in apoptosis, cell cycle and DNA repair. It blocks cell development in response to cellular stress or DNA damage. Many viruses replicate by changing cell cycles and exploiting the same pathways that are altered in cancer cells. The E1B protein produced by adenovirus protects infected cells by binding and lowering the p53 transcription factor, preventing it from targeting cells for apoptosis. This allows the virus to replicate, pack its genome, lyse cells and spread to new cells.
This raises the idea that modified adenovirus can be used to target and eliminate cancer cells. Onyx-015 is an adenovirus developed in 1987 with the E1B gene function unveiled, which means cells infected with Onyx-015 are unable to block the p53 function. If Onyx-015 infects normal cells, with the p53 genes working, it will be prevented from multiplying by the action of the p53 transcription factor. However, if Onyx-015 infects the deficient p53 cells it must be able to survive and replicate, resulting in the destruction of selective cancer cells.
Clinical test
ColoAd1 of PsiOxus Therapeutics has entered Phase I/II clinical studies with its oncolytic vaccine. Phase I of the trial recruited patients with metastatic solid tumors and showed evidence for viral replication within the tumor site after intravenous delivery. The second phase of the ColoAd1 study will involve intra-tumoral versus intravenous injection to check for viral replication, viral spread, tumor necrosis and anti-tumoral immune response (see EU Clinical Test List for more details).
ONYX-015 ( dl 1520 )/H101
The patent for therapeutic use of ONYX-015 is held by ONYX Pharmaceuticals and is used in combination with standard cisplatin and 5-fluorouracil chemotherapeutic agents to combat tumor head and neck. Onyx-015 has been extensively tested in clinical trials, with data showing that it is safe and selective for cancer. However, limited therapeutic effects have been demonstrated after systemic injection and systemic spread of undetectable virus. ONYX-015 when combined with chemotherapy, proved to be effective in the proportion of cases. During this trial a large number of reports appear to challenge the underlying p53-selectivity, with some reports suggesting that in some cancers with wild-type p53 ONYX-015 is actually better than in their mutant p53 counterparts. These reports slowed progress through Phase III trials in the US, but recently China granted the license ONYX-015 for therapeutic use as H101 . Further development of Onyx-015 was abandoned in early 2000, exclusive rights licensed to Chinese company, Shanghai Sunway Biotech. On November 17, 2005, the State Food and Drug Administration of China approved H101, an onyx-015 (E1B-55K/E3B-deleted) oncolytic adenovirus for use in combination with chemotherapy for the treatment of late-stage refractory nasopharyngeal cancer. Outside of China, the drive to the clinic for ONYX-015 has largely been discontinued for financial reasons and until the real mechanism can be found.
See also
- Oncolytic virus
- AAV Oncolytic
- Oncolytic herpes virus
- Viroterapi
References
External links
- Information about Oncolytic adenovirus
Source of the article : Wikipedia
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