Mutation-specific CAR T cells as precision therapy for IGLV3-21^R110 expressing high-risk chronic lymphocytic leukemia

Area of Science:

• Immunology and Cancer Therapy
• Molecular Biology and Genetics

Background:

• Precision cell therapy requires tumor-specific surface neoepitopes, which are rare in cancers.
• B cell receptors (BCR) in lymphoid malignancies can harbor tumor-specific point mutations, enabling targeted therapy.

Purpose of the Study:

• To develop chimeric antigen receptor (CAR) T cells targeting a specific BCR light chain neoepitope (IGLV3-21^R110) in chronic lymphocytic leukemia (CLL).
• To assess the specificity and efficacy of CAR T cells against IGLV3-21^R110 expressing CLL cells and sparing normal B cells.

Main Methods:

• Development of murine and humanized CAR constructs targeting the IGLV3-21^R110 neoepitope.
• Testing CAR T cell efficacy against cell lines and primary CLL cells expressing the target neoepitope.
• In vivo validation in xenograft and humanized mouse models to confirm epitope-selective and safe targeting.

Main Results:

• Engineered CAR T cells eradicated IGLV3-21^R110 expressing cell lines and primary CLL cells.
• CAR T cells showed no cytotoxicity against cells expressing non-pathogenic IGLV3-21^G110 or polyclonal healthy B cells.
• In vivo studies confirmed selective tumor cell killing and demonstrated safety towards human B cells in humanized models.

Conclusions:

• Targeting the IGLV3-21^R110 neoepitope with CAR T cells offers a highly specific therapeutic strategy for a subset of CLL.
• This approach spares normal B cells, suggesting potential for resistance-preventive and biomarker-guided cellular therapies in lymphomas.
• The findings support the development of advanced cell therapies targeting functionally relevant driver mutations in cancer.