Assoc. Prof Dr Mojca Benčina, head of the newly founded Slovenian Centre for the Technologies of Gene and Cell Therapy (CTGCT), gave a speech at the recent 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in Glasgow, Scotland, which is the most important of its kind in Europe with 5,500 participants. She introduced the plans with the Centre based in Ljubljana and presented innovative methods developed at our institute for the up- or down-regulation of CAR-Ts in vivo.
After presenting the partnership project between the Slovenian National Institute of Chemistry (NIC), UCL, UMC Utrecht, Charité and TU Dresden, she focused on highlighting some of the opportunities for new drug development at CTGCT, focussing mainly on therapies for cancer and neurodegenerative disorders.
The NIC’s Department of Synthetic Biology and Immunology is the nest from which the CTGCT was hatched. The department is actively researching various new immunotherapeutic approaches using technologies such as CAR-T, CRISPR, RNA dCAS, various cellular delivery methods and synthetic biology.
In particular, the research focuses on extending existing technologies to tumour markers for other cancer types, improving therapeutic safety by regulating cell function, activating signalling pathways to enhance the immune system response, increasing selectivity for cancer cells and non-viral delivery of CAR-T constructs into the T-cell genome.
The highlight of her presentation was explaining how the NIC research group achieves up- and down-regulation of CAR-T cells in vivo, essentially providing clinicians with an on/off switch for treating patients. Dr Benčina presented the NIC’s findings, which were published in the Nature Group Journal in January this year (Plaper, T., Merljak, E., Fink, T. et al. Designed allosteric protein logic. Cell Discov 10, 8 (2024). https://doi.org/10.1038/s41421-023-00635-y) and described how they managed to downregulate the activity of CAR-T cells (and selected other processes) by inserting a peptide into a loop of a target protein that retains its function.
Dr Benčina continued by also presenting an upregulation solution in which the response of a protein (again to various selected processes including CAR-T) is achieved by inserting a cleaved ligand-binding protein that is only activated when its two halves are rejoined. This reassembly only occurs when we introduce a cognate physiological ligand or a clinically approved drug in vivo. In layman’s terms, the key and the lock come together to activate the effect of the drug. The article on this topic was published by the NIC in Nature Group Journal in September 2022 (Rihtar, E., Lebar, T., Lainšček, D. et al. Chemically inducible split protein regulators for mammalian cells. Nat Chem Biol 19, 64–71 (2023). https://doi.org/10.1038/s41589-022-01136-x).
The implications of such control mechanisms for clinical practise are immense. The challenge for the CTGCT is to get clinicians to recognise this too and join forces to develop new drugs for the unmet needs of patients around the world.