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DECEMBER 8, 2017 - By expressing a secreted form of an EpCAM-specific BiTE molecule in the cancer cells it infects, a novel oncolytic virus both kills cells directly and induces a robust cytotoxic T cell response.
In a research article published in EMBO Molecular Medicine, a group of scientists at the University of Oxford have described a new twist on cancer immunotherapy, combining two independent cell killing approaches in a single therapeutic with high potency and broad applicability. This creative proof of principle study involved “arming” an oncolytic virus, which is already capable of killing cancer cells on its own, with a therapeutic transgene that potentiates tumor killing via the recruitment of cytotoxic T cells. Using xCELLigence Real-Time Cell Analysis to monitor the killing of cancer cells by a variety of engineered constructs, Leonard Seymour and his team demonstrated the efficacy of this two-pronged therapy in ex vivo assays employing pleural effusions and peritoneal ascites from cancer patients. Based on their findings the authors concluded that this potent therapeutic “should be readily transferred into the clinic.”
Owing to their genetic makeup, oncolytic viruses infect and kill cancer cells preferentially over healthy cells. In the case of EnAdenotucirev, an oncolytic Adenovirus chimera which is now in Phase I/II clinical trials, target cancer cells are killed via the pro-inflammatory process of oncosis. Beyond the cancer cell killing that is directly mediated by EnAdenotucirev (EnAd), Seymour’s team surmised that efficacy gains could be achieved by harnessing the pro-inflammatory response induced by oncosis. Towards this end, they inserted within the EnAdenotucirev genome a gene for a bispecific T cell engager (BiTE) that simultaneously binds CD3 on T cells and EpCAM on target tumor cells. Once a tumor cell is infected with this engineered virus (EnAd-EpCAM-BiTE), the BiTE molecule is produced and secreted into the extracellular milieu. As hypothesized, the EnAd-EpCAM-BiTE virus elicited T cell-mediated killing of diverse tumor cell types with very high efficiency, and in a manner that was dependent upon the concentration of EpCAM on target cell surfaces. Importantly, the efficacy of this approach was demonstrated using as assay medium pleural effusions and peritoneal ascites from cancer patients. As these fluids are known to be immunosuppressive, the potency of the EnAd-EpCAM-BiTE virus is particularly impressive and suggests it may also be effective against solid tumors where immune suppression can be a major barrier to treatment.
Beyond the EpCAM-BiTE employed in this study, the authors state that ”viruses offer the potential to encode and express other anticancer biologics, obviating delivery challenges and ensuring the biologic achieves its highest concentration within the tumor microenvironment.” With this in mind, they concluded that “the potential for arming viruses is virtually limitless and provides many exciting opportunities to design multimodal therapeutic strategies with additive or synergistic anticancer effects.” By monitoring target cancer cell killing in real-time and without the use of labels, the automated xCELLigence RTCA assay employed in this study has eliminated the need for laborious endpoint data collection, thereby increasing throughput and accelerating the discovery and optimization of different oncolytic viral constructs armed with diverse therapeutic payloads. With such clear gains in efficacy, these types of viral combination therapies are expected to comprise an increasing percentage of the cancer immunotherapy market in the near future.
The original publication of Seymour and colleagues can be viewed here.
About xCELLigence® RTCA
xCELLigence® Real Time Cell Analysis (RTCA) instruments utilize gold biosensors embedded in the bottom of microtiter wells to non-invasively monitor the status of adherent cells using the principle of cellular impedance. In short, cells act as insulators – impeding the flow of a miniscule electric current between electrodes. This impedance signal is measured automatically, at an interval defined by the user, and provides an extremely sensitive readout of cell number, cell size, cell-substrate attachment strength, and cell invasion/migration. xCELLigence® RTCA instruments are being used in both academia and industry for basic and applied applications ranging from cancer immunotherapy and cardiotoxicity to drug discovery and receptor signaling. To date xCELLigence® has been used in more than 1,400 publications, which can be viewed in a searchable library.
About ACEA Biosciences
Founded in 2002, ACEA Biosciences is a pioneer in the development and commercialization of high performance, cutting edge cell analysis platforms for life science research. ACEA’s xCELLigence® impedance-based, label-free, real-time cell analysis instruments and NovoCyte® flow cytometer are used in pre-clinical drug discovery and development, toxicology, safety pharmacology, and basic academic research. More than 2,000 instruments have been placed globally.