Shengchun Wang, Cosimo Lobello, Pradeep Gupta, Roniya Francis, Aldana Vistarop, Bhaumik Shah, Sergio Zamora-Erazo, Fahad Ahmed, David Rushmore, Andrew Kalgren, David Nelson, Vanessa Dupoux, Johnvesly Basappa, Don A Baldwin, Henry Fung, Mowafaq Jillab, Hayan Lee, K Qi Cai, Reza Nejati, Bijan Boldajipour, Janusz Franco-Barraza, Gary Lee, Kavindra Nath, Mariusz A Wasik
ROR1 is expressed across a broad spectrum of malignancies. While T lymphocytes armed with chimeric antigen receptor targeting ROR1 (CART-ROR1 cells) have reached clinical stage, the efficacy of this therapy has been limited. We report that inhibition of H3K27 methyltransferase EZH2 and, to a much lesser degree, the DNA methyltransferase DNMT1 and the H3K9 methyltransferase G9A promotes ROR1 expression by malignant cells. EZH2 inhibition also directly impairs the growth of some malignant cell populations. The combination of EZH2 inhibition and CART-ROR1 cells is much more effective than CART-ROR1 cells alone in eliminating malignant cells. While EZH2 inhibition variably enhances the expression of immune checkpoint receptors, it markedly increases the synthesis of T cell-activating soluble factors and promotes the cytotoxic phenotype of CART-ROR1 cells. These results indicate that EZH2 inhibition enhances the CART-ROR1 cell effectiveness by diverse mechanisms, including promotion of ROR1 expression by malignant cells, suggesting that the combination may prove clinically more effective than CART-ROR1 cell monotherapy.