Characteristics of the spatio-temporal distributions of chimeric antigen receptor T cells based on real-world evidence Free

Introduction Chimeric antigen receptor (CAR) T cell therapy, which involves the reinfusion of a patient's T cells into their body after these cells have been genetically engineered to target and kill specific tumour cells, has attracted increasing attention from researchers. As living drugs, CAR-T cells undergo spatial and temporal biodistributions, their activation, diffusion, and expansion can influence the clinical efficacy. Therefore, the dynamic monitoring of CAR-T cells in vivo is essential for exploring their distribution and optimizing clinical responses. However, due to the challenges in sampling tissue-resident CAR-T cells from patients, limited data have been reported on their spatial and temporal distribution.

Methods This study included 43 patients with haematological malignancies who received CAR-T cell therapy. To explore the spatial and temporal distributions of CAR-T cells in patients, 210 samples, including 105 serous cavity effusion (SCE) and the time-paired 105 peripheral blood (PB) samples were collected and their CAR transgene copies numbers were sequentially monitored and analyzed.

Results The robust expansion of CAR-T cells in PB was beneficial for the diffusion in SCE. However, the T_max of CAR-T cells in SCE was observed to be delayed compared to that in PB. Patients who experienced immune effector cell-associated neurotoxicity syndrome (ICANS) had greater CAR-T expansion in cerebrospinal fluid (CSF) than did those without ICANS. Peripheral infection promoted CAR-T cell diffusion into CSF and expansion. Our results indicated that tumour invasion related to the local accumulation and expansion of CAR-T cells in pleural effusion or ascites. Moreover, patients with tumour invasion were more likely to experience local CRS (L-CRS).

Conclusions The distribution of CAR-T cells in SCE and PB shows correlation and consistency. A high CAR copies number in the CSF suggests the possibility of ICANS or infection. The differential diagnosis between ICANS and infection should be based on established diagnostic criteria for both conditions. Elevated CAR copies numbers and IL-6 levels in PE/A indicate L-CRS. Therefore, our study enhances the understanding of CAR-T cell diffusion, trafficking, and expansion, offering new insights for clinical diagnosis and treatment.

Keywords CAR-T cells, Spatial and temporal distributions, Serous cavity effusion, Local CRS