Study Pinpoints Protein YTHDF2 As Enabler of Blood Cancer Cell Growth, CAR T-Cell Therapy Escape

YTHDF2, a protein highly involved in blood cancers’ pathobiology, facilitates leukemia and lymphoma cells’ escape of chimeric antigen receptor (CAR) T-cell therapy.¹ This was pinpointed in a study conducted by researchers at Beckman Research Institute of City of Hope, Duarte, California, who have published their findings in Cell.²

According to the study findings, YTHDF2 aids cancer cells’ evasion of CAR T-cell therapy by reducing the antigen biomarkers on those cells that can be targeted by the immune system, such as CD19. This protein also promotes the growth and spread of cancer cells, and in mouse studies, has been observed to convert healthy blood cells to cancer.

“Unraveling the biology underlying YTHDF2’s function will help us develop new strategies to prevent tumor cells from escaping immune surveillance,” explained study first author Zhen-Hua Chen, PhD.¹

The research team expects that their findings will lead to more personalized cancer treatment approaches for patients and improve outcomes. City of Hope is currently developing a compound, CCI-38, to target and suppress YTHDF2. This aims to reduce blood cancer cell growth and escape from CAR T-cell therapy.

“We believe that using CCI-38 to target YTHDF2 will significantly enhance the effectiveness of CAR T cell therapy on blood cancer cells,” said Jianjun Chen, PhD, Center for RNA Biology and Therapeutics Director at Beckman Research Institute.¹

References

1. City of Hope scientists uncover protein that helps cancer cells dodge CAR T cell therapy. News release. Business Wire. December 17, 2024. Accessed January 6, 2025. https://www.businesswire.com/news/home/20241217442267/en/City-of-Hope-Scientists-Uncover-Protein-That-Helps-Cancer-Cells-Dodge-CAR-T-Cell-Therapy
2. Chen Z, Zeng C, Yang L, et al. YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies. Cell. Published online December 12, 2024. doi:10.1016/j.cell.2024.11.007