CAR-iNKT cells targeting clonal TCRVβ chains as a precise strategy to treat T cell lymphoma

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• T cell receptor (TCR) Vβ chain-expressing T cell lymphomas (TCL), including those linked to Human T cell leukaemia virus type-1 (HTLV-1), are associated with poor patient outcomes.
• Current treatment strategies for TCL often lack specificity and can lead to significant side effects due to damage to the healthy T cell repertoire.

Purpose of the Study:

• To investigate the potential of chimeric antigen receptor (CAR)-mediated targeting of clonal T cell receptor (TCR) Vβ chains as a cell therapy for T cell lymphomas (TCL).
• To assess the efficacy and selectivity of CAR-T and CAR-invariant NKT (iNKT) cells in targeting TCL, with a focus on minimizing impact on the physiological TCR repertoire.

Main Methods:

• Generation of CAR constructs designed to target specific TCR Vβ subunits.
• Testing the efficacy of CAR-T cells against conventional T cells and CAR-iNKT cells for their potential in 'off-the-shelf' immunotherapy.
• In vivo studies using CAR-iNKT cells to evaluate their therapeutic effect on TCL growth and their activity against malignant cells from Adult T cell leukaemia/lymphoma patients.

Main Results:

• CAR-T cells demonstrated selective killing of cognate tumor targets, preserving over 90% of the physiological TCR repertoire.
• CAR-iNKT cells effectively inhibited TCL growth in vivo.
• CAR-iNKT cells showed selective activity against malignant cells from Adult T cell leukaemia/lymphoma patients without activating HTLV-1 expression.

Conclusions:

• Proof-of-concept for effective and selective anti-TCRVβ CAR-T cell-based therapy for TCL.
• Demonstration of CAR-iNKT cells as a viable 'off-the-shelf' immunotherapy option for TCL, offering selective tumor targeting and minimal impact on healthy T cells.