Switchable targeting of solid tumors by BsCAR T cells

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Chimeric antigen receptor (CAR) T cell therapy is a significant advancement in cancer treatment.
• CAR T cell therapy faces challenges in solid tumors due to the lack of tumor-specific antigens, leading to on-target, off-tumor effects.
• Spatial separation of cytotoxic functions and antigen recognition offers precise control over CAR T cell activity.

Purpose of the Study:

• To develop a switchable and precisely controlled CAR T cell system for solid tumor therapy.
• To utilize the barnase-barstar bacterial toxin-antitoxin system for guiding CAR T cells to solid tumors.
• To enable multitargeted adoptive immunotherapy with enhanced safety and efficacy.

Main Methods:

• Designed complementary modules: ankyrin repeat (DARPin)-barnase proteins and barstar-based CAR (BsCAR).
• Employed the barnase-barstar system for switchable targeting of tumor cells.
• Varied DARPin-barnase loads to modulate cytokine release and BsCAR T cell cytotoxicity.

Main Results:

• Demonstrated switchable targeting of different tumor antigens using a single BsCAR by altering DARPin-barnase modules.
• Achieved gradual increases in cytokine release and tunable BsCAR T cell cytotoxicity.
• Successfully eradicated HER2+ ductal carcinoma in vivo using switchable BsCAR T cell therapy.

Conclusions:

• The developed switchable BsCAR T cell therapy provides a universal platform for controlled, multitargeted adoptive immunotherapy.
• This approach enhances the safety and efficacy of CAR T cell therapy against solid tumors.
• Precise control over CAR T cell activity is achieved by spatially separating cytotoxic function from antigen recognition.