Periodic Reporting for period 4 - PeptiCrad (Personalized oncolytic vaccines for cancer immunotherapy)
Periodo di rendicontazione: 2021-01-01 al 2022-06-30
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.
During the implementation of the project, my research team and myself have managed to achieve all the main goals proposed in our application. We developed and proved that PeptiCRAd is an efficient platforms to treat different types of cancer in different murine models, we developed a technology for the identification and the prioritisation of tumor-specifc antigens and Neo-antigens and we combine these different technologies in a single pipeline for personalized cancer immunotherapy. The technologies that we have developed during this grant resulted in several tens of publication in prestigious journals, more than 98% of these in open access to allow everybody to read our results and replicate our technologies. In addition to our scientific production we have paid particular attention to the impact that our science would have and we have tried to maximise the impact to benefit the societal and economic growth of our stakeholder. In fact, we submitted more than 30 invention disclosures of which 7 become patents and 5 were fully licensed. Out of our core technology, PeptiCRAd, we founded a spinoff company that is now in clinical trial and that has been mentioned as one of the 15 biotech companies that is driving innovation in Finland.
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.
During the implementation of the project, my research team and myself have managed to achieve all the main goals proposed in our application. We developed and proved that PeptiCRAd is an efficient platforms to treat different types of cancer in different murine models, we developed a technology for the identification and the prioritisation of tumor-specifc antigens and Neo-antigens and we combine these different technologies in a single pipeline for personalized cancer immunotherapy. The technologies that we have developed during this grant resulted in several tens of publication in prestigious journals, more than 98% of these in open access to allow everybody to read our results and replicate our technologies. In addition to our scientific production we have paid particular attention to the impact that our science would have and we have tried to maximise the impact to benefit the societal and economic growth of our stakeholder. In fact, we submitted more than 30 invention disclosures of which 7 become patents and 5 were fully licensed. Out of our core technology, PeptiCRAd, we founded a spinoff company that is now in clinical trial and that has been mentioned as one of the 15 biotech companies that is driving innovation in Finland.
Firstly we have developed and have assessed the efficacy of our technology, PeptiCRAd (Peptide-coated Conditionally Replicating Adenovirus). This technology was thought already with the intention of simplify the clinical translation particularly for personalised cancer therapies, it consists of coating the surface of an engineered oncolytic virus with tumor-specific antigens to direct the viral immune response towards the tumor immune response; in other words, the immune system of the patients gets activated by the presence of the virus, but, as the virus is covered with tumor antigens, instead of promoting a strong anti-viral response and weak anti-tumor response it promotes a strong anti-tumor response and weak anti-viral response. Importantly, PeptiCRAd does not require any genetic modification of the virus to direct the immune response towards different tumor antigens, this allows a very rapid and extremely inexpensive platforms to target different tumor types and different patients. In addition of the development of the "coating strategies" we also generated various engineered viruses with immunological active cargo to orchestrate the tumor microenvironment and make it more susceptible to the immune attack, for example we have developed a virus expressing CD40L/OX40L (to enhance the presentation of the antigens via PeptiCRAd and to activate T cells), we have also developed a virus expressing a chimeric receptor to clock PDL1 to fully unleash the efficacy of the T cell response and finally we have produced viruses with different chemokine to promote T cell infiltration in the tumor microenvironment. In parallel, as envisioned in our application, we developed different methods for the identification and for the prioritisation of the tumor antigens. In fact, we developed the immunopeptidomics technology, that was already known but it was not present in Finland, and we developed PeptiCHIP that is a unique technology for antigen discovery from a very small amount of cells, that is very compatible with real clinical setting and needle biopsies.
All these results have resulted in more than 30 original scientific papers, 7 patents, 5 licensed technologies, 2 ERC-PoC, 1 spinoff company and an ongoing clinical trial.
All these results have resulted in more than 30 original scientific papers, 7 patents, 5 licensed technologies, 2 ERC-PoC, 1 spinoff company and an ongoing clinical trial.
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.
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.