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Personalized oncolytic vaccines for cancer immunotherapy

Periodic Reporting for period 3 - PeptiCrad (Personalized oncolytic vaccines for cancer immunotherapy)

Reporting period: 2019-07-01 to 2020-12-31

"Cancer is a leading cause of death, in fact it has been estimated that by 2040, 63% of the human population would be affected by this disease. New therapies have been developed and especially important are the one that are exploiting our own immune system. The main goal of my ERC-CoG grant is to develop novel class of anti-cancer vaccines based on the use of oncolytic adenoviruses; oncolytic viruses are viruses that can selectively replicate in cancer cells.
In general, it is very well known that humans get viral infections, however our immune system is able to recognize the viruses and eliminate them quite efficiently. On the other hands, our immune system fails to recognize tumors allowing it to grow indiscriminately. This simple observation led me to hypothesize that if I could ""dress"" the viruses as tumors, the immune system would not fail to recognize it. On the contrary, the immune system would trigger an immune response towards the virus and everything that is covering it, including the tumor. With this easy trick I would be able to confuse the immune system making it think that “tumors are viruses to be eliminated”.
In practice, my project takes advantage of viruses that are already widely used in clinic (in clinical trials or as approved drugs) and for which we know efficacy and safety profile and decorate these viruses with tumor-specific antigens. When these viruses are given to the patient, the immune system of the patient recognize them and start an immune response against it BUT, because the virus is now coated with tumor antigens (or neo-antigens) the immune response will be rather direct against the tumor and not the virus. I have called this technology PeptiCRAd (Peptide coated Conditionally Replicating Adenoviruses) and the main aim of this grant application is to develop this technology and to test its efficacy in murine model of solid tumors.
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From the beginning of the project we have been developing and testing in murine model of tumor the feasibility and the efficacy of PeptiCRAd technology. First, we have worked on possible strategies to form the complex between the virus and the tumor antigens, we have also demonstrated that the complex is formed and it is stable enough to be tested in animal models. In animal models of cancer we have tested its efficacy in murine model of melanoma and murine model of triple negative breast cancer. Interestingly we have also shown that peptiCRAd has a synergistic effect with some of the immune checkpoints’ inhibitors that the state-of-art immunotherapy at the moment. Interestingly, in parallel we have been also developing technologies to discover new tumor antigens and neo-antigens to load onto the surface of the adenovirus.
Ideally, in a short future, we will have a pipeline that identify tumor antigens from tumor samples and load them onto viruses for personalized PeptiCRAd formation.
Oncolytic viruses have been in clinic for a long time and it is well known that they can trigger some degrees of anti-tumor immune response, however the quality of this immune response has been one of the most unresolved problem in the field because it could not be found an easy solution to direct the immunological response triggered by the virus towards the tumor. If successful, PeptiCRAd technology would provide an easy and versatile solution to direct the immunological response that follows oncolytic virus treatments towards the desired tumor-antigen. PeptiCRAd could be applied to any adenovirus and with any tumor antigens. The proof-of-concept has been so successful in our first part of the grant this same technology has been patented and it now constitutes the core business of a very successful multimillion startup company (VALO therapeutics, www.valotx.com) that I have funded together with the University of Helsinki. As side project developed by this ERC-based idea, but not necessarily proposed in this grant application, we have also adapted this technology to enveloped viruses (such as vaccinia and herpes viruses) demonstrating a comparable efficacy. We called this other technology PeptiENV; PeptiENV has been also patented and licensed from the University of Helsinki to VALO Therapeutics.
In summary, I have proposed to explore the efficacy of a new technology for therapeutic cancer vaccines based on oncolytic adenoviruses decorated with tumor-specific antigens. In my laboratory we have tested and characterized the feasibility and the efficacy of this technology in various murine tumor models. Moreover, we have patented this technology and this patent has led to a spin-off company that would bring it to clinic for the benefit of real cancer patients.
Abstract image of PeptiCRAd and PeptiENV
Schematic of PeptiCRAd