Cord blood-derived CD19-specific chimeric antigen receptor T cells: an off-the-shelf promising therapeutic option for treatment of diffuse large B-cell lymphoma.

Abstract

Autologous chimeric antigen receptor (CAR) T cell therapy is one of the most significant breakthroughs in hematological malignancies. However, a three-week manufacturing cycle and ineffective T cell dysfunction in some patients hinder the widespread application of auto-CAR T cell therapy. Studies suggest that cord blood (CB), with its unique biological properties, could be an optimal source for CAR T cells, providing a product with 'off-the-shelf' availability. Therefore, exploring the potential of CB as an immunotherapeutic agent is essential for understanding and promoting the further use of CAR T cell therapy. We used CB to generate CB-derived CD19-targeting CAR T (CB CD19-CAR T) cells. We assessed the anti-tumor capacity of CB CD19-CAR T cells to kill diffuse large B cell lymphoma (DLBCL) in vitro and in vivo. CB CD19-CAR T cells showed the target-specific killing of CD19+ T cell lymphoma cell line BV173 and CD19+ DLBCL cell line SUDHL-4, activated various effector functions, and inhibited tumor progression in a mouse (BALB/c nude) model. However, some exhaustion-associated genes were involved in off-tumor cytotoxicity towards activated lymphocytes. Gene expression profiles confirmed increased chemokines/chemokine receptors and exhaustion genes in CB CD19-CAR T cells upon tumor stimulation compared to CB T cells. They indicated inherent changes in the associated signaling pathways in the constructed CB CAR T cells and targeted tumor processes. CB CD19-CAR T cells represent a promising therapeutic strategy for treating DLBCL. The unique biological properties and high availability of CB CD19-CAR T cells make this approach feasible.