Miest Et Al (2013) Nature Reviews Micro 1223

Review

doi: 10.1038/nrmicro1927.

Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded

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• PMID: 18552863
• PMCID: PMC3947522
• DOI: ten.1038/nrmicro1927

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Review

Reprogrammed viruses equally cancer therapeutics: targeted, armed and shielded

Roberto Cattaneo  et al. Nat Rev Microbiol. 2008 Jul .

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Abstract

Virotherapy is currently undergoing a renaissance, based on our improved understanding of virus biology and genetics and our ameliorate noesis of many different types of cancer. Viruses can exist reprogrammed into oncolytic vectors by combining three types of modification: targeting, arming and shielding. Targeting introduces multiple layers of cancer specificity and improves prophylactic and efficacy; arming occurs through the expression of prodrug convertases and cytokines; and coating with polymers and the sequential usage of dissimilar envelopes or capsids provides shielding from the host immune response. Virus-based therapeutics are start to find their place in cancer clinical practice, in combination with chemotherapy and radiation.

Figures

Figure one. Oncolytic viruses that are currently used in cancer clinical trials

The major characteristics of vii families of oncolytic viruses are summarized. Recombinant strains of all the Dna viruses shown are currently in clinical trials, whereas amidst the RNA viruses shown, just recombinant MV is in clinical trials; recombinant poliovirus and VSV are in pre-clinical trials and non-engineered strains of reovirus and NDV are in Stage I–II clinical trials. HSV1, herpes simplex virus i; MV, measles virus; NDV, Newcastle disease virus; VSV, vesicular stomatitis virus.

Figure 2. 4 layers of specificity for retargeting viral tropism

a | Virus particle activation tin can exist reprogrammed to depend on proteases that are secreted by cancer cells. Activation occurs through matrix metalloproteases (MMPs) that are located in the tumour matrix. b | Recombinant viruses tin be engineered to enter cells through a designated receptor rather than through the natural attachment protein. c | Viral transcription and replication can exist fabricated dependent on tissue- or cancer-specific promoters. d | Viruses with modifications or deletions of their immune-evasion proteins replicate preferentially in sure transformed cells. Not every targeting strategy tin can be practical to every virus, but more than and more viruses with combined layers of specificity are being engineered for specific clinical trials.

Figure 3. MV particle structure, genome organization and targeting approaches

The MV genome has half dozen genes that lawmaking for eight proteins. The first cistron codes for the nucleocapsid protein (Northward) that encapsidates the genomic RNA. The concluding cistron (L) codes for the polymerase protein that replicates and transcribes the genome together with the phosphoprotein (P), a polymerase cofactor. The matrix protein (M) organizes virus particle assembly. The two glycoproteins haemagglutinin (H) and the fusion (F) protein contact the receptor and execute membrane fusion, respectively. Two non-structural proteins that are coded by the P factor (C and Five) control the innate immune response. a | Three-dimensional construction of MV H. Residues that are necessary for signalling lymphocytic activation molecule (SLAM)-dependent or CD46-dependent fusion are in red. The site of add-on of the single-chain fragment variable (scFv) is in black. b | A schematic of the P and 5 proteins that are encoded past the P factor. These proteins share their amino-terminal domain, but differ at the carboxyl terminus. The residues of the V and P mutual domain that are of import for the interaction with STAT1 (signal transducer and activator of transcription 1) have been characterized. Three amino acids in a conserved hexapeptide are shown in majestic. Data from the Horvath group indicate that STAT2 and MDA5 interact with different sequences in the unique cysteine-rich domain of V (A. Ramachandran, J-P. Parisien and C.Chiliad. Horvath, unpublished observations). c | Schematic of the MV F protein and amino acid sequences of its cleavage site. The standard F protein is cleaved into F_i and F₂ fragments by furin, a ubiquitous protease. Furin cleavage occurs fifty-fifty subsequently a hexameric peptide that codes for a matrix metalloproteinase 2 (MMP2) cleavage site is introduced (F-MMP), but the resulting F₁ poly peptide, which is extended past six residues, is inactive. Trimming of three amino-terminal residues by MMP2 cleavage confers function to F-MMP.

Figure 4. Adenovirus particle construction, genome organization and targeting approaches

An icosahedral, non-enveloped adenovirus (Ad) particle is shown. The key genes in the viral genome that are relevant to the four targeting approaches discussed in the chief text are indicated. a | Cancer-specific transcription and replication targeting are applied to the E1 and E4 genes. b | Cancer-specific proteolytic activation has not nevertheless been attempted. c | Cancer-specific receptor attachment is mediated by genetic or chemic modification of the IX, penton, hexon or fibre proteins or genes. d | Preferential spread targeting can be based on over-expression of the ADP gene and the insertion of exogenous genes into the viral genome. ITR, inverted terminal echo; MMP, matrix metalloproteinase; Pro, protease.

Effigy 5. Strategies to improve oncolytic virus efficacy

a | Shielding the virus confronting antibodies. Pre-existing neutralizing antibodies in humans can interfere with efficacy. Changing virus serotypes and coating particles with shielding polymers can address the neutralizing-antibody trouble. b | Transient immunosuppression of the host. Infected cells tin can be attacked past macrophages, T cells and natural killer cells. Transient immunosuppression interferes with the activation and ability of these cells to recognize and/or kill infected cells and restrict oncolytic efficacy.

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