What approaches are being considered to improve therapeutic safety?

CAR-T cells, as cytotoxic and immunomodulatory agents, inherently present an element of risk. As such, researchers are working to combat potential therapeutic issues such as non-specific targeting and immune overstimulation. When employing CAR-T cell therapy, clinicians have to be very careful regarding initial dosages and dose escalation in order to carefully manage immune system activation extent and avoid cytokine storms and deleterious inflammation.1,2 One potential method to regulate CAR-T cell activity is the generation of time-sensitive CAR-T cells. These cells would be equipped with inactivation mechanisms – such as transient CAR gene expression or “suicide genes” – to prevent chronic immunoactivation. Alternatively, side effects, especially off-organ targeting, could be limited by increasing CAR-T cell specificity. One promising approach to accomplish this is generating T cells expressing multiple CARs. By targeting an expression pattern instead of a singular antigen, CAR-T specificity for tumor cells can be greatly improved, limiting off-target cellular injury.1

1. G. Dotti, et al., “Design and Development of Therapies using Chimeric Antigen Receptor-Expressing T cells,” Immunol Rev 257(1):10, 2014.
2. J. Hartmann, et al., “Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts,” EMBO Mol Med 9(9):1183-1197, 2017.