Induction of immortal-like and functional CAR T cells by defined factors

Area of Science:

• Immunology
• Cell Biology
• Cancer Therapy

Background:

• Long-term efficacy of chimeric antigen receptor (CAR) T cells relies on their sustained in vivo persistence.
• T cells possessing stem-like properties demonstrate improved persistence, yet the specific factors governing T cell stemness are not fully understood.

Purpose of the Study:

• To investigate the induction of CAR T cells into a novel immortal-like and functional state (TIF).
• To identify the key factors and signaling requirements for inducing this TIF state.
• To evaluate the antitumor efficacy and persistence of these reprogrammed CAR T cells.

Main Methods:

• Demonstrated the induction of CAR T cells into the TIF state.
• Identified the repression of BCOR and ZC3H12A as critical for TIF induction.
• Showcased the requirement of antigen or CAR tonic signaling for reprogramming.
• Assessed the stemness, functionality, and in vivo antitumor effects of CARTIF cells.

Main Results:

• Successfully reprogrammed CAR T cells into an immortal-like and functional state (CARTIF).
• CARTIF cells exhibit near-infinite stemness, comparable to induced pluripotent stem cells, while maintaining mature T cell functionality.
• CARTIF cells demonstrated superior antitumor effects and long-term in vivo persistence, entering a dormant state post-target elimination and providing memory protection.

Conclusions:

• TIF represents a novel T cell state characterized by unprecedented stemness.
• This TIF state confers long-term functional persistence to CAR T cells in vivo.
• The TIF state holds significant potential for advancing CAR T cell therapies.