Multipronged enhancement of CART cell activity against ROR1 neoantigen by inhibition of H3K27 methyltransferase EZH2
5 affiliations
- 1Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- 2Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
- 3Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- 4Department of Bone Marrow Transplant and Cellular Therapy, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- 5Lyell Immunopharma, South San Francisco, CA 94080, USA
Abstract
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.
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BibTeX
@article{wang2026multipronged,
title = {{Multipronged enhancement of CART cell activity against ROR1 neoantigen by inhibition of H3K27 methyltransferase EZH2}},
author = {Shengchun Wang and Cosimo Lobello and Pradeep K. Gupta and Roniya Francis and Aldana Vistarop and Bhaumik Shah and Sergio Zamora-Erazo and Fahad Ahmed and David Rushmore and Andrew Kalgren and David Nelson and Vanessa Dupoux and Johnvesly Basappa and Don A. Baldwin and Henry Fung and Mowafaq Jillab and Hayan Lee and K. Qi Cai and Reza Nejati and Bijan Boldajipour and Janusz Franco-Barraza and Gary Lee and Kavindra Nath and Mariusz A. Wasik},
journal = {Cell Reports Medicine},
year = {2026},
month = sep,
doi = {10.1016/j.xcrm.2026.103060},
url = {https://doi.org/10.1016/j.xcrm.2026.103060},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Multipronged enhancement of CART cell activity against ROR1 neoantigen by inhibition of H3K27 methyltransferase EZH2
AU - Shengchun Wang
AU - Cosimo Lobello
AU - Pradeep K. Gupta
AU - Roniya Francis
AU - Aldana Vistarop
AU - Bhaumik Shah
AU - Sergio Zamora-Erazo
AU - Fahad Ahmed
AU - David Rushmore
AU - Andrew Kalgren
AU - David Nelson
AU - Vanessa Dupoux
AU - Johnvesly Basappa
AU - Don A. Baldwin
AU - Henry Fung
AU - Mowafaq Jillab
AU - Hayan Lee
AU - K. Qi Cai
AU - Reza Nejati
AU - Bijan Boldajipour
AU - Janusz Franco-Barraza
AU - Gary Lee
AU - Kavindra Nath
AU - Mariusz A. Wasik
PY - 2026
DA - 2026/09/25
JO - Cell Reports Medicine
DO - 10.1016/j.xcrm.2026.103060
UR - https://doi.org/10.1016/j.xcrm.2026.103060
AB - 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.
SN - 2666-3791
ER -