Targeting CD123 with CAR-T Cells: Preclinical Efficacy in Blastic Plasmacytoid Dendritic Cell Neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon and aggressive cancer of the blood, arising from immature plasmacytoid dendritic cells. The understanding of its biological nature is limited, and the historical prognosis for patients is poor, with no standard treatment in place. The CD123/IL3Rα protein is excessively present in almost all BPDCN patients. Given the significant medical need for BPDCN patients, targeting CD123 is a promising strategy due to its presence on the cell surface and its high levels in BPDCN cells compared to normal stem cells.

UCART123 is a type of engineered T-cell derived from healthy donors, which contains a receptor that binds to CD123 and a component that makes it vulnerable to the drug rituximab. The T-cells are modified to lack a specific T cell receptor, using a technique that disables a gene involved in its expression. The study aimed to test the effectiveness of these allogeneic anti-CD123 CAR-T cells in BPDCN.

The expression of CD123 was measured in the bone marrow of newly diagnosed BPDCN patients and compared to that in AML patients, showing notably higher levels in BPDCN.

The cytotoxic effect of UCART123 was assessed in vitro by mixing them with BPDCN cells and observing the cells' ability to kill the target cells, which was significantly greater than that of non-engineered T-cells.

The study also examined the ability of UCART123 to release a protein associated with cell killing when exposed to BPDCN cells, which was found to be specific and significant.

Furthermore, the T-cells' capacity to produce a cytokine in response to BPDCN cells was tested, with UCART123 cells showing a strong production of IFNγ when stimulated by CD123 positive BPDCN cells.

In vivo testing using mice with transplanted BPDCN showed that UCART123 cells significantly prolonged survival and reduced tumor presence. After treatment, UCART123 cells were found in the spleen and bone marrow of the mice.

In conclusion, UCART123 has shown specific anti-tumor activity against BPDCN cells, with evidence of T-cell activation and cytokine production. The cells also demonstrated persistence in the body and contributed to tumor eradication and long-term survival in mice. The study suggests that UCART123 CAR T-cells have potential in treating BPDCN and warrants further clinical evaluation. Additional studies are ongoing and will be reported.