Gene modification strategies for next-generation CAR T cells against solid cancers

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy
• Gene Editing

Background:

• Chimeric antigen receptor (CAR) T-cell therapy is highly effective against hematological cancers but faces challenges in solid tumors.
• Key barriers include antigen targeting, the immunosuppressive tumor microenvironment (TME), and CAR T-cell infiltration, proliferation, and persistence.

Purpose of the Study:

• To review innovative strategies for enhancing CAR T-cell function against solid tumors using gene-editing technology.
• Focus on improving target identification, persistence, trafficking, and overcoming the suppressive TME.

Main Methods:

• Construction of multi-target CAR T cells for improved antigen recognition and reduced immune escape.
• Enhancement of CAR T-cell proliferation and persistence via optimized costimulatory signals and cytokine overexpression.
• Engineering CAR T cells with chemokines or chemokine receptors for improved tumor homing.
• Strategies to counteract the TME, including knockout of immune checkpoint molecules and incorporation of dominant-negative or chimeric switch receptors.

Main Results:

• Multi-target CAR T cells demonstrate improved antigen recognition and reduced tumor immune escape.
• Optimized costimulatory signals and cytokine overexpression enhance CAR T-cell proliferation and persistence.
• Engineered CAR T cells exhibit improved tumor site homing.
• Gene-editing strategies effectively overcome TME-mediated suppression.

Conclusions:

• Gene-editing technologies are crucial for developing next-generation CAR T cells with enhanced antitumor properties for solid tumors.
• These strategies collectively address major barriers, paving the way for broader clinical application of CAR T-cell therapy.