Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells

Area of Science:

• Immunology
• Cellular Biology
• Oncology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematologic malignancies but suffers from high relapse rates.
• T-cell dysfunction is a major contributor to CAR T-cell treatment failure.
• Previous research implicated sustained CAR CD3ζ signaling in T-cell dysfunction.

Purpose of the Study:

• To investigate mechanisms driving CAR T-cell dysfunction beyond sustained signaling.
• To explore the role of excessive costimulation in CAR T-cell failure.
• To identify strategies for optimizing CAR T-cell efficacy.

Main Methods:

• Activated CD19-targeted CAR T cells were stimulated with endogenous and CAR-mediated CD28 costimulation.
• CAR T-cell dysfunction was assessed in a syngeneic immunocompetent mouse model.
• CAR T cells were activated using signals 1 (CD3ζ), 2 (CD28), and 3 (IL12).

Main Results:

• Excessive CD28 costimulation, alongside CD3ζ signaling, induced CAR T-cell dysfunction.
• CAR T-cell dysfunction was observed in vivo in a mouse model.
• Both CD28 and 4-1BB costimulation were identified as drivers of CAR T-cell dysfunction.

Conclusions:

• Excessive costimulation is a critical mechanism leading to CAR T-cell dysfunction.
• This finding provides new insights into CAR T-cell failure.
• Targeting costimulatory pathways may enhance CAR T-cell therapy efficacy and reduce relapse rates.