Oncolytic virotherapy is a therapeutic strategy that uses modified or naturally selected viruses to preferentially infect tumour cells. Once inside, these viruses replicate, destroying cancer cells and stimulating an immune response against the tumour. Specific, effective and synergistic with the immune system, it is the perfect cocktail. As a result, oncolytic viruses have been evaluated in numerous clinical trials in recent years, with some already reaching clinical practice.
However, this type of therapy faces a significant challenge: after systemic administration, only a small fraction of the therapeutic viruses successfully reaches the tumour. When viruses are administered intravenously, many are neutralized by the immune system or eliminated before arriving their destination. As foreign agents, the immune system is designed to recognize and eliminate them. One possible solution is to protect them during the journey by hiding or “disguising” them. For this reason, researchers have been investigating the use of mesenchymal stem cells as vehicles capable of transporting these viruses more efficiently to tumours.
This is the approach that pioneered more than a decade ago by the team of Dr. Rafael Moreno, from the Cancer Immunotherapy group at IDIBELL and ICO, and which has now taken a step further in a study recently published in Molecular Therapy Oncology. With CONAN (Controlled-replication ONcolytic AdeNovirus), Dr. Moreno and his team have developed a new technology that modifies both the carrier cell and the oncolytic virus itself. The system not only improves the efficient and stealthy delivery of oncolytic viruses to tumours, but also enables researchers to control viral activation on demand in order to maximize therapeutic efficacy.
The development of this technology has been possible thanks to the participation of the Spanish Gynecological Cancer Research Group and the support of the Spanish Association Against Cancer (AECC), the 2025 XarSMART-VSTO Awards, the Carlos III Health Institute, and the Generalitat de Catalunya through the Gínjol – CERCA 2023 patent fund.
An improved Trojan Horse
CELYVIR, the first approach in which Dr. Moreno’s team participated and which has been developed over more than two decades, laid the foundation. It functioned as a “Trojan Horse“: mesenchymal cells acted as carriers, transporting oncolytic viruses inside them to the tumor, where the viruses were released and attacked cancer cells. The system proved effective and was evaluated both in compassionate-use trial –meaning exceptional administration in patients with no remaining therapeutic options–, and in clinical trials.
However, this Trojan Horse had an important limitation. Viruses could become activated too early, replicating within the carrier cells themselves and destroying them before they had enough time to reach the tumour. As a result, much of the viral cargo was lost along the way and only a small amount reached its target.
CONAN provides a solution by enabling temporal control over oncolytic virus activation. The system suppresses viral replication while mesenchymal cells travel toward the tumor, and reactivated it later through the administration of the commonly used antibiotic doxycycline. “CONAN is an improved Trojan Horse. It allows more horses to reach the tumour in better conditions and tells the viruses when the best moment is to come out“, explains Dr Rafael Moreno.
A switch to delay viral replication
In other words, CONAN incorporates an additional layer of control through a genetic regulatory system that determines when viral replication begins. To achieve this, both the vehicles and their cargo must be modified: mesenchymal cells are engineered to express a repressor protein (TetR) while oncolytic viruses are designed to include specific DNA sequences (TetO) within their genome.
Thus, while the virus is inside the carrier cell, TetR acts as a molecular brake by binding to TetO and preventing viral replication. Once the tumor is reached, administration of doxycycline causes TetR to detach from TetO, releasing the brake and allowing the virus to replicate again. “Essentially, this is an on-off system that we can control through antibiotic administration. When doxycycline is given, the system is unlocked and switches from “off” to “on”, enabling viral replication. Moreover, once the virus is allowed to replicate and is released from the carrier cell within the tumour, these viruses no longer have a braking system. They can therefore infect and multiply freely within tumour cells, achieving the desired antitumour effect”, says Dr Moreno.
The results show that CONAN effectively delays viral replication within carrier cells without compromising the virus’s ability to replicate later in tumour cells. Consequently, in preclinical models of lung adenocarcinoma, CONAN increased viral accumulation within tumours and improved antitumour activity compared with non-regulated strategies. According to the team’s data, by day eight day of treatment, tumorus showed up to 13 times greater viral production, which was associated with a 64% improvement in antitumour efficacy. In a second independent experiment, the improvement reached 54%.
A flexible platform for different virotherapy approached
Beyond the specific model tested in this study, researchers emphasize that one of CONAN’s main advantages is its plasticity. The technology was developed using menstrual blood-derived stem cells and a specific adenovirus (ICOVIR15), “but its modular design could allow adaptation to other oncolytic viruses and different carrier cell types,” Moreno insists. This flexibility opens the door to virotherapy approaches that are more easily tailored to different tumour types, routes of administration, and/or clinical needs.
In this sense, CONAN is envisioned as the latest technological advancement that could be incorporated into CELYVIR. The extensive experience accumulated through this strategy, including manufacturing, safety assessment, and clinical evaluation, may serve as a springboard for the development of this new generation of controllable virotherapies. “CONAN should be understood as an improved version of CELYVIR,” summarizes Dr. Moreno. “It builds on everything we have learned from this strategy and adds a layer of control that can make it more precise, more effective, and much more adaptable.”
However, it is important to note that CONAN remains in the preclinical stage. Because it involves genetic modifications to both the carrier cells and the virus, additional regulatory evaluations will be required before it can be tested in patients. “This is a complex strategy that would very likely improve upon the results obtained with CELYVIR, but there is still work to be done before it reaches the clinic,” concludes the researcher.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research centre created in 2004 specialising in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from the 73 research groups, generate more than 1,400 scientific articles per year. IDIBELL is supported by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).