Chimeric Antigen Receptor (CAR) T cell therapy involves re-engineering patient-derived T cells to redirect T cell cytotoxicity against tumour cells. Whilst CAR T cell therapy has demonstrated remarkable success in treating haematological malignancies, the same success has not yet been recapitulated in solid tumours, including brain tumours. To enhance CAR T therapy strategies, it is crucial to understand the dynamics of CAR T cells within the tumour microenvironment and their interactions with other cellular players.
We have established a chronic cranial window implant, which provides a window into the brain of immunocompetent mouse model of glioma (Mulazzani et al, 2019, PNAS). In combination with two-photon microscopy, this allows us to visualize tumour cell growth intravitally, longitudinally over the entire tumour course. We can examine the extent of T cell infiltration, accumulation, directionality, velocity, and persistence across time in the same mouse.
We found that antigen-specific CAR T cells can infiltrate and accumulate in the brain as early as two days after infusion, but the CAR T cells did not show migration towards or away from tumour; instead, they travelled along tumour border. Despite our in vitro T cell killing assays demonstrating CAR T cell effectiveness, they were unable to clear the tumour in vivo and the mice all eventually succumbed to disease. This suggests a possibility of other cellular players within the tumour microenvironment hindering T cells cytotoxicity, emphasising the need for combination therapy approaches.
This cutting-edge in vivo intravital imaging technique allows us to gain new insights into the complex interactions between CAR T cells and other immune cells and tumour cells within the brain microenvironment, which can ultimately inform the development of more effective immunotherapies for brain tumours.