Targeting CCR9 with CAR-T Therapy: A Promising Approach for T-ALL Treatment

The abstract discusses the limited treatment options for relapsed/refractory T acute lymphoblastic leukemia (T-ALL), highlighting the success of CD19-directed CAR-T cell therapy for B-ALL in contrast. The challenge with CAR-T therapy for T-ALL lies in finding antigens not expressed on normal T cells to prevent cell loss and self-harm.

Researchers pursued immunotherapy targets for T-ALL by analyzing gene expression profiles of normal tissues and comparing them to MOLT-4, a T-ALL cell line. Through subtractive transcriptomics, they identified 12 unique transcripts in MOLT-4, with CCR9 being a promising candidate due to its expression on the cell surface and absence in normal tissues.

Further analysis confirmed CCR9 expression in over 70% of pediatric T-ALL cases. CCR9 is a receptor found in gut intraepithelial γδ T cells, certain dendritic cells, and thymocytes, but is rare in normal circulating T and B cells and absent in hematopoietic stem cells and myeloid cells.

Flow cytometry showed CCR9 expression in 73% of primary T-ALL cases, with higher expression in relapsed/refractory cases. Normal blood cells had minimal CCR9 expression.

A novel anti-CCR9 scFv was developed, and a second-generation CAR was created with a 4-1BB-CD3ζ endodomain. T cells with anti-CCR9 CAR expanded like controls and showed no self-harm. CARCCR9 cells demonstrated cytotoxicity, cytokine secretion, and proliferation against CCR9+ T-ALL cell lines, even at low target density.

In vivo testing in mice showed that CARCCR9 cells led to disease regression, weight gain, and prolonged survival, unlike untreated mice or those receiving control CAR19 cells. Re-injection of MOLT4-Fluc showed sustained anti-leukemic effects.

Testing in two patient-derived xenograft (PDX) models of T-ALL also showed CARCCR9's effectiveness, with recipients showing undetectable leukemia and long-term survival, unlike those with untreated or CAR19 cells.

The study concludes that anti-CCR9 CAR-T cells could offer a safe and effective treatment for T-ALL, marking a significant step forward in an under-addressed clinical field.