An oncolytic adenovirus redirected with a tumor-specific T-cell receptor.
To improve safety and specificity of oncolytic adenoviruses, we introduced T-cell receptors (TCR) specific for a unique class of truly tumor-specific antigens into the adenoviral fiber protein. The adenoviral fiber knob responsible for attachment to the coxsackie-adenoviral receptor (CAR) on target cells was replaced by a single-chain TCR (scTCR) molecule with specificity for the melanoma-associated cancer-testis antigen MAGE-A1, presented by HLA-A1, and an extrinsic trimerization motif in a replicating Ad5 vector (Ad5.R1-scTCR). The production of the recombinant virus was initiated in a novel producer cell line that expressed an antibody-based hexon-specific receptor (293T-AdR) in the cell membrane. This new production system allowed CAR-independent and target antigen-independent propagation of Ad5.R1-scTCR. Infection with adenovirus bearing the scTCR-based fiber resulted in an efficient killing of target tumor cells. The infection was cell type specific because only HLA-A1(+)/MAGE-A1(+) melanoma cells were killed, and thus, this retargeting strategy provides a versatile tool for future clinical application.
Tumor Immunology Group, Unit of Clinical and Tumor Immunology, Department of Medical Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.
Zsolt
Z
Sebestyen
Jeroen
J
de Vrij
Maria
M
Magnusson
Reno
R
Debets
Ralph
R
Willemsen
D000256:Adenoviridae / Q000502:physiology*; D000257:Adenoviridae Infections / Q000276:immunology / Q000628:therapy / Q000821:virology*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005434:Flow Cytometry; D005822:Genetic Vectors; D015788:HLA-A1 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000276:immunology / Q000628:therapy / Q000821:virology*; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism; D050130:Oncolytic Virotherapy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D011991:Receptors, Virus / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D000951:Antigens, Neoplasm; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015788:HLA-A1 Antigen; C072011:MAGEA1 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D011991:Receptors, Virus