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Preprint WatchMildSeptember 1st, 2026

Disruption of the interferon-gamma axis limits chimeric antigen receptor T cell efficacy against acute myeloid leukemia

Murren, N.; King, I.; Mahoney, L.; Roy, J.; Kletzien, O. A.; Collins, M.; Geffe, S.; Kalcheim, L.; Richards, R.

Interferon-gamma signalling is required for CD123 target antigen upregulation on AML blasts, so blocking interferon-gamma to control CAR T toxicity also removes the antigen density that the therapy depends on.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The mechanistic claim is that CD123 surface density on AML blasts is inducible and interferon-gamma dependent, which makes antigen availability a treatment-conditional variable rather than a fixed patient characteristic. The Claidex graph holds one IL3RA failure, Sanofi's CD123 T cell engager SAR443579, which was stopped for strategic reasons rather than on efficacy grounds (sar443579-il3ra-cd123-aml-phase1-2-strategic-termination). Because that termination was not an efficacy readout, this preprint neither contradicts nor rescues the prior record. It does raise a design question for the next CD123-directed program. If antigen density depends on an inflammatory signal that toxicity management is designed to suppress, then baseline CD123 expression is a weak enrolment criterion and any concurrent anti-inflammatory strategy needs an explicit antigen-density monitoring plan.

Abstract excerpt

Despite the success of chimeric antigen receptor (CAR) T cell therapy for treatment of B cell acute lymphoblastic leukemia (B-ALL), its translation to acute myeloid leukemia (AML) has been hindered by limited efficacy and significant toxicity. Interferon-gamma (IFN{gamma}) blockade with emapalumab has recently emerged as a promising strategy to mitigate CAR T cell-related toxicities in B cell malignancies, based on evidence that IFN{gamma} is largely dispensable for optimal CAR T cell activity in B-ALL. Whether IFN{gamma} signaling is similarly non-essential in the AML context remains unclear. Here, we demonstrate that disruption of the IFN{gamma} axis impedes anti-AML CAR T cell function and prevents upregulation of target antigen CD123, the apoptotic mediator Fas, and the adhesion molecule ICAM-1 on AML cells. Conversely, exogenous IFN{gamma} enhances CAR T cell cytotoxicity and increases CAR T cell avidity for AML targets. These findings identify IFN{gamma} as a critical mediator of CAR T cell efficacy against AML by promoting increased target antigen expression, enhanced cytotoxicity, and stable CAR T/tumor interactions. Our results suggest that therapeutic IFN{gamma} blockade, including with emapalumab, may compromise CAR T cell responses in AML and should be approached with caution in this disease context.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.