Pseudotyped αvβ6 integrin-targeted adenovirus vectors for ovarian cancer therapies

Uusi-Kerttula, Hanni; Davies, James A.; Coughlan, Lynda; Hulin-Curtis, Sarah; Jones, Rachel; Hanna, Louise; Chester, John D.; Parker, Alan L.

doi:10.18632/oncotarget.8545

Cited by 39 publications

(54 citation statements)

References 65 publications

(112 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All vectors generated in this study included a luciferase (Luc) reporter gene. Genetic modifications were carried out by AdZ homologous recombineering methods (29) as described previously (30). Viruses were produced in T-REx-293 or HEK293-b6 cells (for A20-modified viruses) and purified as described previously (30,31).…”

Section: Adenovirus Vectors Cell Lines and Clinical Ascitesmentioning

confidence: 99%

“…Genetic modifications were carried out by AdZ homologous recombineering methods (29) as described previously (30). Viruses were produced in T-REx-293 or HEK293-b6 cells (for A20-modified viruses) and purified as described previously (30,31). A triply detargeted vector genome, Ad5 NULL , was generated by introducing mutations in key genes encoding of each of the major capsid proteins to preclude cellular uptake by all known native Ad5 pathways.…”

Section: Adenovirus Vectors Cell Lines and Clinical Ascitesmentioning

confidence: 99%

“…Primary EOC cells from ascites were obtained through Wales Cancer Bank under existing ethical permissions (WCB 14/004). Cells were processed and subcultured as described previously (30,31), and tested regularly for Mycoplasma infection by commercially available PCR-based methods.…”

Section: Adenovirus Vectors Cell Lines and Clinical Ascitesmentioning

confidence: 99%

See 2 more Smart Citations

Ad5NULL-A20: A Tropism-Modified, αvβ6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies

Uusi-Kerttula

Davies

Thompson

et al. 2018

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for the manipulability and tolerance of transgenes. Poor tumor selectivity, off-target sequestration, and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumor-selective virotherapy targeted to αvβ6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but nondetectable in healthy tissues. Ad5-A20 harbors mutations in each major capsid protein to preclude uptake via all native pathways. Tumor-tropism via αvβ6 targeting was achieved by genetic insertion of A20 peptide (NAVPNLRGDLQVLAQKVART) within the fiber knob protein. The vector's selectivity and was assessed. The tropism-ablating triple mutation completely blocked all native cell entry pathways of Ad5-A20 via coxsackie and adenovirus receptor (CAR), αvβ3/5 integrins, and coagulation factor 10 (FX). Ad5-A20 efficiently and selectively transduced αvβ6 cell lines and primary clinical ascites-derived EOC , including in the presence of preexisting anti-Ad5 immunity. biodistribution of Ad5-A20 following systemic delivery in non-tumor-bearing mice was significantly reduced in all off-target organs, including a remarkable 10-fold reduced genome accumulation in the liver compared with Ad5. Tumor uptake, transgene expression, and efficacy were confirmed in a peritoneal SKOV3 xenograft model of human EOC, where oncolytic Ad5-A20-treated animals demonstrated significantly improved survival compared with those treated with oncolytic Ad5. Oncolytic Ad5-A20 virotherapies represent an excellent vector for local and systemic targeting of αvβ6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors. .

show abstract

Section: Adenovirus Vectors Cell Lines and Clinical Ascitesmentioning

confidence: 99%

Section: Adenovirus Vectors Cell Lines and Clinical Ascitesmentioning

confidence: 99%

See 1 more Smart Citation

Ad5NULL-A20: A Tropism-Modified, αvβ6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies

Uusi-Kerttula

Davies

Thompson

et al. 2018

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although some virus-derived vectors, such as Semliki Forest virus, have a natural tropism toward tumors, those derived from measles virus, retroviruses and adenovirus can be engineered to specifically target tumors, which could reduce side effects due to systemic injection, especially by restricting transduced cell types. Several polypeptides have been used for vector surface-engineering, among which are antibodies and cytokines [100,101,[103][104][105][106][107]. For example, antibodies targeting tissue-specific or tumor-specific markers (e.g., HER2) have been used to control vector tropism in vivo in breast tumors.…”

Section: Appendix a Antibodies To Restrict Vector Tropism To Tumor Cementioning

confidence: 99%

Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

Page

Fusil

Cosset

2020

Cancers

View full text Add to dashboard Cite

Cancers represent highly significant health issues and the options for their treatment are often not efficient to cure the disease. Immunotherapy strategies have been developed to modulate the patient’s immune system in order to eradicate cancerous cells. For instance, passive immunization consists in the administration at high doses of exogenously produced monoclonal antibodies directed either against tumor antigen or against immune checkpoint inhibitors. Its main advantage is that it provides immediate immunity, though during a relatively short period, which consequently requires frequent injections. To circumvent this limitation, several approaches, reviewed here, have emerged to induce in vivo antibody secretion at physiological doses. Gene delivery vectors, such as adenoviral vectors or adeno-associated vectors, have been designed to induce antibody secretion in vivo after in situ cell modification, and have driven significant improvements in several cancer models. However, anti-idiotypic antibodies and escape mutants have been detected, probably because of both the continuous expression of antibodies and their expression by unspecialized cell types. To overcome these hurdles, adoptive transfer of genetically modified B cells that secrete antibodies either constitutively or in a regulated manner have been developed by ex vivo transgene insertion with viral vectors. Recently, with the emergence of gene editing technologies, the endogenous B cell receptor loci of B cells have been modified with the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonuclease (Cas-9) system to change their specificity in order to target a given antigen. The expression of the modified BCR gene hence follows the endogenous regulation mechanisms, which may prevent or at least reduce side effects. Although these approaches seem promising for cancer treatments, major questions, such as the persistence and the re-activation potential of these engineered cells, remain to be addressed in clinically relevant animal models before translation to humans.

show abstract

“…The replication deficient (E1/E3) adenovirus vectors Ad5-DNAJB7 (expressing the entire DNAJB7 ORF (open reading frame)) and Ad5-EMPTY (lacking an inserted ORF) were generated in the AdZ vector system, using homologous recombineering methods as previously described (34,35). The DNAJB7 ORF was gene synthesized by GeneArt (ThermoFisher Scientific, UK), prior to being inserted into the AdZ vector.…”

Section: Adenovirus Vectors and Cell Linesmentioning

confidence: 99%

Cancer Antigen Discovery Is Enabled by RNA Sequencing of Highly Purified Malignant and Nonmalignant Cells

Scurr

Greenshields‐Watson

Campbell

et al. 2020

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Broadly expressed, highly differentiated tumor-associated antigens (TAA) can elicit anti-tumor immunity. However, vaccines targeting TAAs have demonstrated disappointing clinical results, reflecting poor antigen selection and/or immunosuppressive mechanisms. Experimental design: Here, a panel of widely expressed, novel colorectal TAAs were identified by performing RNA sequencing of highly purified colorectal tumor cells in comparison to patient-matched colonic epithelial cells; tumor cell purification was essential to reveal these genes. Candidate TAA protein expression was confirmed by immunohistochemistry, and pre-existing T cell immunogenicity towards these antigens tested. Results: The most promising candidate for further development is DNAJB7 [DnaJ heat shock protein family (Hsp40) member B7], identified here as a novel cancertestis antigen. It is expressed in many tumors and is strongly immunogenic in patients with cancers originating from a variety of sites. DNAJB7-specific T cells were capable of killing colorectal tumor lines in vitro, and the IFN- + response was markedly magnified by control of immunosuppression with cyclophosphamide in cancer patients. Conclusion: This study highlights how prior methods that sequence whole tumor fractions (i.e. inclusive of alive/dead stromal cells) for antigen identification may have limitations. Through tumor cell purification and sequencing, novel candidate TAAs have been identified for future immunotherapeutic targeting.

show abstract

Pseudotyped αvβ6 integrin-targeted adenovirus vectors for ovarian cancer therapies

Cited by 39 publications

References 65 publications

Ad5NULL-A20: A Tropism-Modified, αvβ6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies

Ad5NULL-A20: A Tropism-Modified, αvβ6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies

Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

Cancer Antigen Discovery Is Enabled by RNA Sequencing of Highly Purified Malignant and Nonmalignant Cells

Contact Info

Product

Resources

About