Oncolytic adenovirus

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Further information: Oncolytic virus

Adenovirus varieties have been explored extensively as a viral vector for gene therapy and also as an oncolytic virus.[1]

Of the many different viruses being explored for oncolytic potential, an adenovirus was the first to be approved by a regulatory agency, the genetically modified H101 strain. It gained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer.[2][3]

Engineering of oncolytic adenovirus

Adenoviruses have so far been through three generations of development.[4] Some of the strategies for modification of adenoviruses are described below.

Attenuation

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.[citation needed]

A conditionally replicative adenovirus (CRAd) with a 24 base pair deletion in the retinoblastoma-binding domain of the E1A protein (Ad5- Δ24E3), is unable to silence retinoblastoma, and therefore unable to induce S-phase in host cells.[5] This restricts Ad5-Δ24E3 to replication only in proliferating cells, such as tumour cells.[citation needed]

Targeting

The most commonly used group of adenoviruses is

epithelial cells, CAR expression in tumours is extremely variable, leading to resistance to Ad5 infection.[6] Retargeting of Ad5 from CAR, to another receptor that is ubiquitously expressed on cancer cells, may overcome this resistance.[6]

  • Adapter molecules
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.[7] 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.[citation needed]
  • Coat-protein modification
This method involves genetically modifying the fiber knob domain of the viral coat protein to alter its specificity. Short
oesophageal adenocarcinoma.[8][9] When combined with a form of non-transductional targeting, these viruses proved to be effective and selective therapeutic agents for Oesophageal Adenocarcinoma.[citation needed
]
  • Transcriptional targeting
This approach takes advantage of deregulated promoter to drive and control the expression of adenoviral genes. For instance,
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).[9] 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.[citation needed
]
A suitable tumour-specific promoter for prostate cancer is prostate-specific antigen (PSA), whose expression 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. The CN706 titre is significantly greater in PSA-positive cells.[10]
  • Post-Transcriptional detargeting
Oncolytic adenovirus controlled by microRNA response element
Another layer of regulation that has emerged to control adenoviral replication is the use of microRNAs (miRNA) artificial target sites or miRNA response elements (MREs). Differential expression of miRNAs between healthy tissues and tumors permit to engineer oncolytic viruses in order to have their ability to replicate impaired in those tissues of interest while allowing its replication in the tumor cells.
Tissue/cell-type Enriched miRNA Use of the MRE References
Liver miR-122 Prevent liver toxicity, hepatotoxicity [11]
Muscle miR-133, miR-206 Prevent muscle inflammation, myositis [12]
Pancreas miR-148a Promote pancreatic tumor targeting [13]
Prostate miR-143, miR-145 Promote prostate tumor targeting [14]
Neuron miR-124 Promote astrocyte targeting [15]

Arming with Transgenes

To enhance the efficacy, therapeutic transgenes are integrated into oncolytic adenovirus[16]

  • stimulation of immune response

Immunostimulatory genes Like interferon α (IFNα),[17] tumor necrosis factor alpha (TNFα),[18] and interleukin 12 (IL-12)[19] have been integrated into oncolytic adenovirus to enhance immune response inside the tumor microenvironment. When these molecules selectively expressed in tumor cells, oncolytic adenoviruses promote immune responses against tumor and minimize systemic side effects [20]

  • Enhancement of Ag presentation

Oncolytic adenoviruses have been genetically modified with transgene encoding for granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance tumor antigens presentation by antigen-presenting cells (APCs). This approach aims to improve recognition of tumor by T-cell and subsequent immune responses [21],[22]

  • Targeting costimulatory and Immune Checkpoints on T-cells

Oncolytic adenoviruses have been genetically engineered to express checkpoint inhibitors (CTLA-4, anti-PD-L1 antibodies) to release brake of T-cell activity [23],[24] and to express costimulatory molecules (CD40L, 4-1BBL) to augment T-cell activation and proliferation[25],[26]

Examples

Oncorine (H101)

H101 and the very similar Onyx-015 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.[3] Despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially.[3] While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone.[3] It appears to work best when injected directly into a tumour, and when any resulting fever is not suppressed.[3] Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease.[27] It is now marketed under the brand name Oncorine.[28]

Onyx-015 (dl1520)

Onyx-015 (originally named Ad2/5 dl1520

cancer cells.[32]

Directed Evolution

Traditional research has focussed on species C Adenovirus serotype 5 (Ad5) for creating

oncolytic vaccines for the potential use as cancer treatment. However, recent data suggests that it may not be the best virus serotype for deriving all oncolytic agents for treating human malignancies.[33] For example, oncolytic vaccines based on the Ad5 serotype have relatively poor clinical efficacy as monotherapies.[34][35][36][37] The need for increased potency (infectivity and lytic activity) has led to an expanded search involving a larger number of less well studied adenovirus serotypes.[citation needed
]

ColoAd1

One non-species C oncolytic

ColoAd1. It was created using a process of “directed evolution”. This involves the creation of new viral variants or serotypes specifically directed against tumour cells via rounds of directed selection using large populations of randomly generated recombinant precursor viruses. The increased biodiversity produced by the initial homologous recombination step provides a large random pool of viral candidates which can then be passed through a series of selection steps designed to lead towards a pre-specified outcome (e.g. higher tumor specific activity) without requiring any previous knowledge of the resultant viral mechanisms that are responsible for that outcome.[38]
One particular application of this approach produced ColoAd1, which is a novel Ad11p/Ad3 chimeric Group B oncolytic virus with specificity for human
colon cancer and a broad spectrum of anti-cancer activity in common solid tumours.[38]
The therapeutic efficacy of ColoAd1 is currently being evaluated in three ongoing clinical trials (see the EU Clinical Trials Register for further details). ColoAd1 potency can be further enhanced via the use of therapeutic transgenes, which can be introduced into the ColoAd1 genome without compromising the selectivity or activity of the virus. Recent studies with ColoAd1 have shown a unique mechanism of cell death similar to Oncosis with expression of inflammatory cell death markers and cell membrane blistering and have highlighted mechanisms by which ColoAd1 alters host cell metabolism to facilitate replication.[39][40]

Background

genes involved in cell cycle control and apoptosis accumulate over time.[41] Most tumours studied, have defects in the p53 tumor suppressor pathway.[42] p53 is a transcription factor that plays a role in apoptosis, cell cycle and DNA repair. It blocks cell progression in response to cellular stress or DNA damage. Many viruses replicate by altering the cell cycle and exploiting the same pathways that are altered in cancer cells.[43] E1B proteins produced by adenoviruses protect the infected cell by binding to and degrading the p53 transcription factors,[44] preventing it from targeting the cell for apoptosis. This allows the virus to replicate, package its genome, lyse the cell and spread to new cells.[citation needed
]

This gave rise to the idea that an altered adenovirus could be used to target and eliminate cancer cells.

normal
cell, with a functioning p53 gene, it will be prevented from multiplying by the action of the p53 transcription factor. However, if Onyx-015 infects a p53 deficient cell it should be able to survive and replicate, resulting in selective destruction of cancer cells.

Clinical trials

There are as of 2023 several ongoing and finished clinical trial testing oncolytic adenoviruses.[46][47][48]

ColoAd1
from PsiOxus Therapeutics has entered Phase I/II clinical study with its oncolytic vaccine. Phase I of the trial recruited patients with metastatic solid tumors and showed evidence for virus replication within tumour sites after intravenous delivery. The second phase of the ColoAd1 study will involve the comparison of intra-tumoural versus intravenous injection to examine viral replication, viral spread, tumour necrosis and anti-tumoural immune responses (see the EU Clinical Trials Register for further details).

ONYX-015 (dl1520)/H101

Patents for the therapeutic use of

nasopharyngeal cancer.[55][56] 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.[57]

See also

References

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External links

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