Journal Article

Oncolytic adenovirus expressing bispecific antibody targets T‐cell cytotoxicity in cancer biopsies

Scott, Eleanor M, Spiers, Laura, Miller, Paul, Kanellakis, Nikolaos, Fisher, Kerry D, Hagel, Joachim, Seymour, Leonard W, Freedman, Joshua D, Ashfield, Rebecca, Psallidas, Ioannis, Duffy, Margaret R, Gupta, Avinash

2017

Overview

Oncolytic viruses exploit the cancer cell phenotype to complete their lytic life cycle, releasing progeny virus to infect nearby cells and repeat the process. We modified the oncolytic group B adenovirus EnAdenotucirev (EnAd) to express a bispecific single‐chain antibody, secreted from infected tumour cells into the microenvironment. This bispecific T‐cell engager (BiTE) binds to EpCAM on target cells and cross‐links them to CD3 on T cells, leading to clustering and activation of both CD4 and CD8 T cells. BiTE transcription can be controlled by the virus major late promoter, limiting expression to cancer cells that are permissive for virus replication. This approach can potentiate the cytotoxicity of EnAd, and we demonstrate using primary pleural effusions and peritoneal malignant ascites that infection of cancer cells with the BiTE‐expressing EnAd leads to activation of endogenous T cells to kill endogenous tumour cells despite the immunosuppressive environment. In this way, we have armed EnAd to combine both direct oncolysis and T cell‐mediated killing, yielding a potent therapeutic that should be readily transferred into the clinic. Synopsis Oncolytic adenovirus “EnAdenotucirev” was armed to express a bispecific T‐cell engager (BiTE) targeting T cells to EpCAM + cancer cells. This strategy mediated rapid cytotoxicity to cancer cells by tumour‐associated T cells and could overcome immune suppressive effects of malignant tumour exudates. Viruses can be “armed” without losing oncolytic potency to express and secrete BiTEs only in cells supporting virus replication. BiTE‐expressing virus can mediate targeted killing of tumour cells in clinical cancer biopsies by exogenous PBMC or endogenous T cells. BiTE‐mediated cytotoxicity in primary malignant exudates is independent of tumour‐associated immune suppression. Graphical Abstract Oncolytic adenovirus “EnAdenotucirev” was armed to express a bispecific T‐cell engager (BiTE) targeting T cells to EpCAM + cancer cells. This strategy mediated rapid cytotoxicity to cancer cells by tumour‐associated T cells and could overcome immune suppressive effects of malignant tumour exudates.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: adenovirus / Adenoviruses / Adenoviruses, Human - genetics / Antibodies / Antibodies, Bispecific - genetics / Antibodies, Bispecific - metabolism / Ascites / Biopsy / bispecific T‐cell engager / BiTE / Cancer / CD3 antigen / CD3 Complex - metabolism / CD4 antigen / CD8 antigen / Cell activation / Cytotoxicity / EMBO03 / EMBO16 / EMBO19 / Epithelial Cell Adhesion Molecule - metabolism / Exudates / Gastric cancer / Genetic crosses / Health aspects / Humans / Immunologic Factors - genetics / Immunologic Factors - metabolism / Immunosuppression / Immunotherapy - methods / Life cycles / Lymphocytes / Lymphocytes T / Molecular Targeted Therapy - methods / Neoplasms - therapy / Oncolysis / Oncolytic Virotherapy - methods / oncolytic virus / Oncolytic Viruses - genetics / Peripheral blood mononuclear cells / Peritoneum / Protein Binding / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Replication / Research Article / T cells / T-Lymphocytes, Cytotoxic - immunology / Transcription / Tumor Cells, Cultured / Tumors / Viral antibodies / Viruses