Yan Leyfman, MD, Hematology-Oncology Fellow at NewYork-Presbyterian Brooklyn Methodist Hospital, shared on X:
“What if resistance to CAR-T therapy begins before treatment even starts?
CD19-directed CAR-T cells have transformed the treatment of large B-cell lymphoma. Yet fewer than half of patients achieve durable responses, underscoring how much remains to be understood about resistance.
A new study sheds light on the role of RHOA loss, a genetic alteration enriched in lymphomas that progress after CAR-T, and also frequently found in newly diagnosed disease.
The investigators show that RHOA deficiency contributes to resistance through at least two mechanisms:
Tumor-intrinsic resistance: RHOA loss downregulates CD19, weakening the target recognition on which CAR-19 therapy depends.
Impaired immune responsiveness: Single-cell analyses reveal that although the tumor microenvironment produces increased interferon-γ (IFNγ), RHOA-deficient lymphoma cells respond poorly to the cytokine, including failing to induce Class I MHC molecules.
The reduction in CD19, however, does not fully explain resistance – or why RHOA deletions are already common in newly diagnosed disease.
The broader insight is that CAR-T resistance may reflect more than loss of the target antigen. Tumor genetics can also shape how malignant cells interact with and respond to their immune environment.
By connecting a recurrent genetic alteration to both antigen expression and defective immune signaling, this work offers a more integrated view of why CAR-19 therapy fails – and points toward mechanisms that may need to be addressed beyond CD19 alone.”
Title: RHOA Deletion Downregulates CD19 and Promotes Dysfunctional Immune Microenvironments in CAR-T Resistant Large B-cell Lymphomas
Authors: Austin D. Newsam, Bachisio Ziccheddu, Abdessamad A. Youssfi, Venu Venkatarame Gowda Saralamma, Santiago Foos-Russ, Daniel E. Tsai, Isaiah Sheffield-Veney, Adithi Jeevan, Paola Manara, Yitzhar E. Goretsky, David M. Suissa, Marco Vincenzo Russo, Nikolai Fattakhov, David Carmona-Berrio, Natalia Campos Gallego, Caroline A. Coughlin, Anya K. Sondhi, Evan R. Roberts, Jay Y. Spiegel, Juan Pablo Alderuccio, Catalina Amador, Daniel Bilbao, David G. Coffey, Michael D. Jain, Francesco Maura, Frederick L. Locke, Jonathan H. Schatz
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