TY - JOUR

T1 - Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment

AU - Osipov, Ivan D.

AU - Vasikhovskaia, Valeriia A.

AU - Zabelina, Daria S.

AU - Kutseikin, Sergei S.

AU - Grazhdantseva, Antonina A.

AU - Kochneva, Galina V.

AU - Davydova, Julia

AU - Netesov, Sergey V.

AU - Romanenko, Margarita V.

N1 - Funding: The research has been supported by Russian Ministry of Science and Higher Education by basic funding grants number FSUS-2020-0035 and FSUS-2022-0021, RSCF Grant number 22-14-00146, FMBA Agreement number 0373100122119000038, NIH NCI R01CA228760, and University of Minnesota Masonic Cancer Center CRTI Translational Research Award.

PY - 2023/1/7

Y1 - 2023/1/7

N2 - Human Adenovirus type 6 (HAdV-C6) is a promising candidate for the development of oncolytic vectors as it has low seroprevalence and the intrinsic ability to evade tissue macrophages. However, its further development as a therapeutic agent is hampered by the lack of convenient cloning methods. We have developed a novel technology when a shuttle plasmid carrying the distal genome parts with modified E1A and E3 regions is recombined in vitro with the truncated HAdV-C6 genome. Using this approach, we have constructed a novel Ad6-hT-GM vector controlled by the hTERT promoter and expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of 6.7K and gp19K E3 proteins. We have demonstrated that control by the hTERT promoter may result in delayed viral replication, which nevertheless does not significantly change the cytotoxic ability of recombinant viruses. The insertion of the transgene by displacing the E3-6.7K/gp19K region does not drastically change the expression patterns of E3 genes; however, mild changes in expression from major late promoter were observed. Finally, we have demonstrated that the treatment of human breast cancer xenografts in murine models with Ad6-hT-GM significantly decreased the tumor volume and improved survival time compared to mock-treated mice.

AB - Human Adenovirus type 6 (HAdV-C6) is a promising candidate for the development of oncolytic vectors as it has low seroprevalence and the intrinsic ability to evade tissue macrophages. However, its further development as a therapeutic agent is hampered by the lack of convenient cloning methods. We have developed a novel technology when a shuttle plasmid carrying the distal genome parts with modified E1A and E3 regions is recombined in vitro with the truncated HAdV-C6 genome. Using this approach, we have constructed a novel Ad6-hT-GM vector controlled by the hTERT promoter and expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of 6.7K and gp19K E3 proteins. We have demonstrated that control by the hTERT promoter may result in delayed viral replication, which nevertheless does not significantly change the cytotoxic ability of recombinant viruses. The insertion of the transgene by displacing the E3-6.7K/gp19K region does not drastically change the expression patterns of E3 genes; however, mild changes in expression from major late promoter were observed. Finally, we have demonstrated that the treatment of human breast cancer xenografts in murine models with Ad6-hT-GM significantly decreased the tumor volume and improved survival time compared to mock-treated mice.

KW - ADENOVIRUS TYPE 6 (HADV-C6; AD6)

KW - adenoviral genome modification

KW - cloning

KW - oncolytic virus

KW - virotherapy

KW - Promoter Regions, Genetic

KW - Oncolytic Virotherapy/methods

KW - Humans

KW - Seroepidemiologic Studies

KW - Oncolytic Viruses/genetics

KW - Animals

KW - Neoplasms/therapy

KW - Virus Replication

KW - Adenoviridae/genetics

KW - Adenoviruses, Human/genetics

KW - Genetic Vectors/genetics

KW - Cell Line, Tumor

KW - Mice

KW - Transgenes

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85147045803&origin=inward&txGid=4ce3491f7947bab0be8f6db11b283656

UR - https://www.elibrary.ru/item.asp?id=50458471

UR - https://www.mendeley.com/catalogue/3d8e5122-9abd-3f03-bb1a-3b4293ba9d22/

U2 - 10.3390/v15010182

DO - 10.3390/v15010182

M3 - Article

C2 - 36680222

VL - 15

JO - Viruses

JF - Viruses

SN - 1999-4915

IS - 1

M1 - 182

ER -