CAR T-cells and Stem-cell Superpowers
Introduction:
Over the past decades, traditional cancer therapy has been limited to chemotherapy and radiation, which has its own set of side effects and limitations. However, with the introduction of chimeric antigen receptor (CAR)-T cell therapy, a new revolutionizing pillar in cancer treatment has been constructed. CARs are engineered synthetic receptors that consist of four main components: an extracellular antigen-binding domain, a hinge region, a transmembrane domain, and one or more intracellular signalling domains depending on which generation it is (R. C. Sterner and R. M. Sterner, 2021). Their function is to redirect lymphocytes, most commonly T cells derived from a patient, to recognize and eliminate cells expressing a specific target antigen. The binding of CAR to target antigens expressed on the cell surface is not limited to the MHC receptor resulting in vigorous T-cell activation and powerful anti-tumor responses to induce the recognition and destruction of cancer cells (R. C. Sterner and R. M. Sterner, 2021). However, it is not without any limitations. CAR T cells still face issues such as their limited efficacy against solid tumours, inhibition and resistance in B cell malignancies, antigen escape, poor persistence, poor trafficking and tumour infiltration, and the immunosuppressive microenvironment (R. C. Sterner and R. M. Sterner, 2021)(D. Sun et al., 2024). Nonetheless, as a form of personalized immunotherapy, CAR T-cell therapy has shown to be successful, as exemplified by anti-CD19 CAR-T cell therapy against B cell malignancies being approved by the US Food and Drug Administration (FDA) in 2017 (R. C. Sterner and R. M. Sterner, 2021).
Figure 1: Schematic of the side effects of CAR T-cells. Taken from: Sterner, R.C. & Sterner, R.M. (2021) CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal. Available from: doi:10.1038/s41408-021-00459-7.
FOXO1 and Stem-cell Superpowers:
Recently, two independent teams of researchers have found that bioengineering CAR T-cells to overexpress FOXO1, a memory transcription factor, promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved persistence and therapeutic efficacy in vivo (Doan, A. et al., 2024)(Chan, J. et al, 2024). The overexpression of FOXO1 resulted in the gene activity of the CAR T cells resembling that of T memory stem cells. The researchers then injected the engineered cells into mice with various types of cancer. Extra FOXO1 made the CAR T cells better at reducing both solid tumours and blood cancers. The in vivo efficacy of this was demonstrated in mice studies where these stem-cell-like cells shrank a mouse’s tumour more and lasted longer in the body than did standard CAR T-cells. Overall, the results from the two teams suggest that FOXO1 represents a major therapeutic axis that can be utilized to enhance the efficacy of T-cell-based cancer immunotherapies. This is an exciting prospect to explore as engineering CAR T-cells that overexpress FOXO1 might be fairly simple to test in people with cancer, but researchers will still need to determine which people and types of cancer are most likely to respond well to said cells.
Article prepared by: Melisa Wong, MBIOS R&D Associate 23/24
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References
Chan, J. D. et al. (2024) FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy. Available from: https://doi.org/10.1038/s41586-024-07242-1 (2024).
Doan, A. et al. (2024) FOXO1 is a master regulator of memory programming in CAR T cells. Available from: https://doi.org/10.1038/s41586-024-07300-8.
Sterner, R.C. & Sterner, R.M. (2021) CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal. Available from: doi:10.1038/s41408-021-00459-7
Sun, D., Shi, X., Li, S., Wang, X., et al. (2024) CAR‑T cell therapy: A breakthrough in traditional cancer treatment strategies (Review). Molecular Medicine Reports. Available from: doi:10.3892/mmr.2024.13171.
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