Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic...

Area of Science:

• Immunology
• Cell Biology
• Oncology

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise for B cell malignancies.
• Identifying T cell subsets with enhanced clinical activity is crucial for optimizing CAR T cell therapy.

Purpose of the Study:

• To identify and characterize a subset of multifunctional CD8+ T cells (CD8-fit T cells) with superior functional capacity for cell therapy.
• To validate the presence, persistence, and clinical relevance of CD8-fit T cells in patients undergoing CAR T cell treatment.

Main Methods:

• Integrated functional profiling using timelapse imaging microscopy in nanowell grids.
• Subcellular profiling and single-cell RNA sequencing of T cells from patients with large B cell lymphoma.
• Validation using independent datasets to assess CD8-fit T cell presence and association with clinical outcomes.

Main Results:

• A signature of multifunctional CD8+ T cells (CD8-fit T cells) was identified, characterized by migratory capacity, serial killing ability, and balanced organelle volumes.
• CD8-fit T cells were found pre-manufacture and associated with positive clinical responses in patients treated with axicabtagene ciloleucel.
• These cells demonstrated longitudinal persistence post-CAR T cell therapy and exhibited tumor-migrating and cytolytic capabilities with intratumoral expansion in solid tumors.

Conclusions:

• Multimodal integration of single-cell functional assessments is powerful for discovering optimal T cell subsets for cell therapy.
• CD8-fit T cells represent a promising T cell subset with optimal fitness for enhancing the efficacy of CAR T cell therapies in both hematological malignancies and solid tumors.