Disruption of the interferon-gamma axis limits chimeric antigen receptor T cell efficacy against acute myeloid leukemia
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…
Chimeric antigen receptor (CAR) T cell therapy has proven effective against B cell acute lymphoblastic leukemia, yet its application to acute myeloid leukemia (AML) has faced challenges due to limited efficacy and high toxicity. Recent research suggests that emapalumab, an interferon-gamma (IFN{gamma}) blocker, could help alleviate CAR T cell-related side effects in B cell malignancies, as IFN{gamma} appears to be less crucial for optimal CAR T cell activity in B-ALL.
However, the role of IFN{gamma} in AML remains uncertain. This study reveals that inhibiting the IFN{gamma} signaling pathway hinders CAR T cell function against AML, preventing the upregulation of target antigen CD123, the production of the apoptotic mediator Fas, and the adhesion molecule ICAM-1 on AML cells. On the other hand, administering exogenous IFN{gamma} boosts CAR T cell toxicity and enhances CAR T cell binding to AML targets.
These findings underscore the critical role of IFN{gamma} in CAR T cell efficacy against AML by stimulating target antigen expression, improving cytotoxicity, and maintaining CAR T cell interactions with tumors. The researchers conclude that therapeutic IFN{gamma} blockade, such as emapalumab, may negatively impact CAR T cell responses in AML and should be used cautiously in this disease context.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
