An international team works on “ATTACK”, the research project funded with 10 million euro by the ERC
Four research groups with complementary and cutting-edge expertise in different areas of immunology, new scientific challenges and development of innovative technologies: these are the winning ingredients of ATTACK, the acronim of “Analysis of the T cell’s Tactical Arsenal for Cancer Killing”, the research project in which the University of Siena participates, funded for 10 million euros by the European Research Council in the context of the Synergy Grants.
The objective of the project is to explore more in depth the mechanisms of T cell-mediated cytotoxicity as the foundation for the development of effective and accessible therapies for the treatment of cancer. In particular, the researchers are working on the development of supramolecular attack particles (SMAP), a new type of biological weapon released by cytotoxic T cells able to kill cancer cells.
The international team and the new challenges – In the laboratories of the Universities of Siena, Oxford, Saarland and Toulouse four teams of young and motivated researchers are working with dedication and enthusiam on ATTACK, in an active interplay where they share reagents and techniques and interact remotely on a daily basis. Periodically they visit the other laboratories of the consortium to carry out collaborative experiments and receive training in new techniques for specific applications.
“The new challenges posed by the project – explains Cosima Baldari, Full Professor of Molecular Biology at the department of Life Sciences at Siena University who coordinates the research together with her colleagues Jens Rettig (Saarland University, Homburg, Germany), Michael Dustin (University of Oxford, United Kingdom) and Salvatore Valitutti (INSERM, CRCT-IUCT, Toulouse, France) – have been met as an opportunity for growth in a context of international excellence, which will strongly enhance the potential of career development in academia or biotec for these young scientists”.
“The Siena team which, in addition to staff scientists, initially included two early career researchers recruited thanks to the grant, has since expanded to include other lab members who work with dedication and participate enthusiastically in the monthly consortium meetings, where they present their results to a highly international audience. Two of them – adds Prof. Baldari- have already spent a research period at Oxford and Toulouse, not only generating results that will be part of collaborative publications, but also bringing back new cutting-edge technologies that have now been implemented in our laboratories”.
“The grant – explains Prof. Baldari- represented for the lab that I lead at the University of Siena a unique opportunity to make a quantum leap, with the purchase of a super resolution fluorescence microscope that allows us to compete with the most outstanding groups in the international scene, while also identifying us as one of the extremely few reference groups in Italy. The purchase of this large piece of equipment, which costs over a million euro, would not have been possible with the standard research grants. The microscope allows for a detail of resolution that makes it possible not only to study the structure of the nanoparticles which are the focus of this research project -the SMAPs-, but also to identify unexplored features of cellular processes that could not be studied by conventional fluorescence microscopy. Implementing the super resolution technology has required specific training that is still ongoing, as we are developing together with the instrument specialists several non-conventional applications required for the project”.
The discovery – The project capitalizes on the recent discovery by members of the ATTACK consortium of a new mechanism of cancer cell killing by cytotoxic T lymphocytes. These are cells of the immune system that coordinate the defenses against cancer and viral infections through a set of toxic molecules that selectively induce the death of tumoral or infected cells without damaging neighbouring healthy cells. The key players in the new defense mechanism discovered by ATTACK are nanoparticles produced by cytotoxic T lymphocytes, the SMAPs, that are released by these cells and are able to kill cancer cells even after cytotoxic T lymphocytes have been removed.
“These features – says Prof. Baldari – have suggested to us the possibility to develop SMAPs as a new therapeutic strategy that can overcome a major limitation in cancer immunotherapy based on the use of engineered T lymphocytes, the CAR T cells”. “In CAR T cell therapy -she continues- T lymphocytes from a patient are modified to ‘force’ them to recognize and kill the tumoral cells and are then re-infused into the patient. Despite the spectacular success of this approach, it cannot be easily implemented in that it strictly requires T lymphocytes from the patient who has to undergo treatment to avoid problems of rejection. Conversely, SMAPs have a peculiar composition that allows for their use to kill cancer cells without the risk of rejection. Additionally, they are very stable, even at room temperature. Thus, if we succeed in engineering them to make them specific for a give type of cancer, SMAPs could become a new ‘universal’ anti-tumoral drug that can be be easily distributed without shelflife problems“.
This strategy can be extended to viral infections for which the COVID-19 pandemic has underscored the need to have as many weapons as possible available to fight the virus.
The future and the role of the University of Siena – The project is very ambitious as it tackles an area completely unexplored to date. This reflects the main feature of the Synergy Grants, which are extremely competitive and are destined to the development of highly innovative research ideas.
To achieve the project objectives over the 6-year duration of the project, new concepts and new technologies will be developed.
“Characterizing the mechanisms through which SMAPs are assembled and kill target cells –states Prof. Baldari- will provide the foundation for their engineering to make them specific for the tumor we want to treat and for their large-scale production”.
In this context the University of Siena plays a key role, as the Siena team will engineer the SMAPs to make them a new, powerful ‘biological weapon’ to add to the arsenal for the fight against cancer.
“The Siena team– adds Prof. Baldari – has already succeeded in modifying the SMAPs to allow for the selective recognition of tumoral cells of chronic lymphocytic leukemia, a blood cancer that we have been studying for many years. Together with our collaborators we are now working on their production to understand whether SMAPs efficiency kill the leukemic cells”.
“Given the potential transferability of the results of the project to other pathological contexts, and in particular to viral diseases, –concludes Prof. Baldari- the project has also triggered an extremely productive collaboration with the group of Prof. Rino Rappuoli, which has already led to a landmark publication of extreme relevance to our understanding of the mechanisms by which the virus SARS-CoV-2, the causative agent of COVID-19, evades our immune defenses. This collaboration has opened an innovative research path that offers the young team members new opportunities to participate in pioneering research”.
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 951329)