Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• B-cell malignancies often resist therapy due to upregulated B-cell lymphoma 2 (Bcl-2) family inhibitors, which block intrinsic apoptosis.
• Small-molecule Bcl-2 inhibitors (e.g., ABT-737) can restore apoptosis in cancer cells.
• Chimeric antigen receptor (CAR) T-cell therapy shows potential for B-cell malignancies by inducing extrinsic apoptosis.

Purpose of the Study:

• To investigate if Bcl-2 family inhibitors can potentiate the efficacy of CAR T-cell therapy in B-cell malignancies.
• To determine if combining intrinsic and extrinsic apoptosis pathways enhances anti-cancer effects.

Main Methods:

• Generated CD19-targeting CAR T cells from healthy donors and pre-B acute lymphoblastic leukemia (pre-B-ALL) patients.
• Tested CAR T cells with ABT-737 against five B-cell tumor cell lines with varying apoptosis resistance.
• Analyzed apoptosis inhibitor expression using PCR and western blot.

Main Results:

• CAR T cells demonstrated effectiveness across cell lines with different apoptosis resistance profiles.
• Simultaneous or sequential administration of ABT-737 with CAR T cells significantly increased tumor cell apoptosis.
• The combination therapy overcame apoptosis resistance mechanisms.

Conclusions:

• The Bcl-2 inhibitor ABT-737 enhances the efficacy of CAR T-cell therapy in B-cell malignancies.
• Combining ABT-737 with CAR T cells represents a promising therapeutic strategy to potentiate T-cell therapy by engaging both intrinsic and extrinsic apoptosis pathways.