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

Abstract

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.

CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment

“…Two recent studies engineered an oncolytic adenovirus to secrete an EGFR-targeting BiTE. The BiTE-expressing adenovirus induced a strong T-cell response against cancer cells both in vitro and in vivo (99,100). The use of oncolytic virus in combination with BiTE or the oncolytic virus secreting BiTE is another strategy for changing the tumor microenvironment.…”

Effect of Transgene Location, Transcriptional Control Elements and Transgene Features in Armed Oncolytic Adenoviruses

“…An OAd armed with an EGFR-targeting BiTE showed promising results alone [70] or in combination with CAR-T cell therapy [143]. OAds expressing BiTEs against Epcam [144] or FAP [71] antigens were also reported. NG-641 (Table 1) currently in a clinical trial is armed with 4 transgenes: Interferon alpha (IFNα) to drive dendritic cell priming, CXCL9 and CXCL10 to recruit T-cells and FAP-BiTE to redirect them.…”

Solid Tumor Immunotherapy with T Cell Engager‐Armed Oncolytic Viruses

“…While very encouraging, these studies describe efficient killing of target tumor cells using exogenous T cells, which may not be representative of the clinical situation in which patient T cells are subject to immunosuppression. Recent work from our laboratory, using EnAd encoding a BiTE targeted to EpCAM, demonstrate that the EpCAM‐BiTE can overcome immune‐suppressive effects associated with the TME . The EpCAM‐BiTE was capable of activating endogenous T cells to target and kill tumor cells in primary human samples of malignant peritoneal ascites and pleural exudates isolated from cancer patients with various indications .…”

“…Recent work from our laboratory, using EnAd encoding a BiTE targeted to EpCAM, demonstrate that the EpCAM‐BiTE can overcome immune‐suppressive effects associated with the TME . The EpCAM‐BiTE was capable of activating endogenous T cells to target and kill tumor cells in primary human samples of malignant peritoneal ascites and pleural exudates isolated from cancer patients with various indications . The impressive efficacy observed by the EnAd‐BiTE combination in such a challenging experimental setting is a very promising indicator for successful translation into the clinic.…”