Innovative CAR T cell cancer immunotherapy (CARRS)

Cancer immunotherapy based on autologous T cells engineered to produce chimeric antigen receptors (CARs) have demonstrated excellent efficiency for a limited type of hematological cancers. CAR T cell therapy represents one of the success stories of synthetic biology, with excellent clinical translational potential, as the cellular responsiveness can be tuned and new types of regulation introduced. This project aims to design and test several innovative strategies of synthetic biology, to increase the safety and efficacy and expand this type of therapy to additional types of cancer, to a) design CARs that will be less sensitive to the antigen escape, b) modify CAR signaling pathways by engineering transmembrane domains, c) introduce alternative signaling domains to limit T cell exhaustion, d) introduce completely humanized regulators of T cell activity to prevent the excessive activation that can cause adverse effects or provide rest to T cells, e) combine CAR signaling with innate immunity pathways, f) test the designs in cell lines, primary T cells and in animal models and g) prepare the regulatory clinical trial framework for most successful designs. Project is based on collaboration between synthetic biologists, immunologists and clinicians, motivated to translate advances in synthetic biology and immunology towards patients. Members of the consortium have recently collaborated on acquiring funding for instruments for the preparation of therapeutic T cells for therapy of ALL and DLBCL, which will be operational in 2022. Project tasks are allocated to interdisciplinary teams with major clinician’s input at the beginning and preparation of regulatory requirements to support the efficient translation to clinics. Project combines extension of the existing CARs to additional hematologic indications that could be most rapidly translated into the clinical application and more ambitious innovative strategies to provide safer and more efficient technological platforms, that could be used also for other types of cancer. We expect that the tools developed here could in the future also contribute to make CAR T cell therapy more appropriate for solid tumors. Several aims, (e.g. WP3 and WP4), will provide insights into the mechanisms of signaling of CAR T cells and alternative signal pathway rewiring, particularly as some key questions on the molecular mechanisms on signal initiation are still not completely understood, such as e.g. on the minimal signaling cluster size, engagement of diverse downstream signaling pathways or role of the transmembrane domains in signaling. The proposed strategies and synthetic biology tools in this project, are aimed to be robust, with a small number of components, that could be delivered by a lentiviral single vector and, importantly, based on human proteins, therefore their persistence of T cells expressing those components in the body should be better in comparison to the ectopic (microbial or plant) receptors, which should prevent elimination of cells expressing foreign antigens. Despite ambitious goals, the existing preliminary results in all major directions of the research and excellent team members support feasibility of the project. We expect that this project will achieve scientific advances and demonstrate the benefits of public science funding.