CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cell therapy targeting CD19 is effective against B cell malignancies.
• Tumor relapse due to CD19 antigen loss limits the long-term efficacy of CD19-directed CAR T cell therapies.

Purpose of the Study:

• To develop and evaluate novel CAR T cells targeting B cell activating factor receptor (BAFF-R) as an alternative strategy to overcome CD19 antigen loss.
• To assess the efficacy of BAFF-R-CAR T cells against CD19-negative B cell malignancies.

Main Methods:

• Development of humanized, second-generation CAR T cells targeting BAFF-R.
• In vitro cytotoxicity assays against human lymphoma and acute lymphoblastic leukemia (ALL) cell lines.
• In vivo studies using tumor xenograft models, including those with CD19-negative variants and patient-derived xenografts (PDXs).

Main Results:

• BAFF-R-CAR T cells demonstrated potent cytotoxicity against human lymphoma and ALL cell lines.
• Adoptive transfer of BAFF-R-CAR T cells eradicated established tumors and retained efficacy against CD19-deficient xenografts.
• BAFF-R-CAR T cells were effective against relapsed ALL with CD19 antigen loss, activating in response to BAFF-R while CD19-CAR T cells did not.

Conclusions:

• B cell activating factor receptor (BAFF-R) is a viable target for CAR T cell therapy in B cell malignancies.
• Targeting BAFF-R may prevent the emergence of CD19 antigen loss variants and overcome resistance to CD19-directed therapies.
• BAFF-R-CAR T cells offer a promising therapeutic strategy for patients with relapsed or refractory B cell cancers, particularly those with antigen escape.