Post-infusion CAR T_Reg cells identify patients resistant to CD19-CAR therapy

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise for large B cell lymphoma but faces challenges with disease progression (approx. 60% of patients) and neurotoxicity.
• Limited biomarkers exist to predict resistance or toxicity in CAR T cell therapy.

Purpose of the Study:

• To identify novel biomarkers associated with clinical response and toxicity in patients undergoing CD19-CAR T cell therapy.
• To investigate the characteristics and clinical relevance of specific CAR T cell subsets.

Main Methods:

• Single-cell proteomic profiling of circulating CAR T cells from 32 patients treated with CD19-CAR T cell therapy.
• Analysis of CAR T regulatory (T_Reg) cell expansion and correlation with clinical outcomes (disease progression, neurotoxicity).
• Development and validation of a predictive model combining CAR T_Reg cells and lactate dehydrogenase levels.

Main Results:

• Expansion of CD4⁺Helios⁺ CAR T cells (identified as CAR T_Reg cells) on day 7 post-infusion was associated with progressive disease and less severe neurotoxicity.
• The CAR T_Reg cell population was found to be non-clonal and exhibited T_Reg cell hallmarks.
• A predictive model incorporating CAR T_Reg cell expansion and lactate dehydrogenase levels demonstrated superior accuracy in predicting durable clinical response.

Conclusions:

• CAR T_Reg cell expansion serves as a novel biomarker for predicting response and toxicity following CAR T cell therapy.
• This subset may play a regulatory role in human CAR T cell responses.
• Further research into CAR T_Reg cells could optimize CAR T cell therapy strategies.