Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Solid tumors develop adaptive resistance by upregulating coinhibitory ligands, hindering T cell-mediated immune responses.
• Chimeric antigen receptor (CAR) T cell therapy, while promising, is often compromised by this adaptive resistance in the tumor microenvironment.
• Programmed death-1 (PD-1)-mediated T cell exhaustion is a key mechanism of resistance affecting CAR T cell efficacy.

Purpose of the Study:

• To investigate the impact of PD-1-mediated T cell exhaustion on mesothelin-targeted CAR T cells in solid tumors.
• To explore cell-intrinsic strategies for overcoming PD-1-mediated inhibition of CAR T cells.
• To evaluate the efficacy of PD-1/PD-1 ligand (PD-L1) pathway interference in restoring CAR T cell function.

Main Methods:

• Utilized an orthotopic mouse model of pleural mesothelioma to assess CAR T cell therapy.
• Compared CD28- and 4-1BB-based second-generation CAR T cells at varying doses.
• Interfered with the PD-1/PD-L1 pathway using PD-1 antibody blockade, PD-1 shRNA, and a dominant-negative PD-1 receptor.

Main Results:

• High doses of both CD28 and 4-1BB CAR T cells achieved tumor eradication; however, PD-1 upregulation inhibited T cell function at lower doses.
• 4-1BB CAR T cells demonstrated prolonged cytotoxic and cytokine secretion functions compared to CD28 CAR T cells at lower doses, correlating with improved survival.
• Interference with the PD-1/PD-L1 pathway successfully restored the effector function of CD28 CAR T cells.

Conclusions:

• PD-1-mediated T cell exhaustion significantly impairs CAR T cell efficacy in solid tumors like mesothelioma.
• 4-1BB costimulation offers a potential advantage over CD28 costimulation in maintaining CAR T cell function under PD-1 inhibitory pressure.
• Targeting the PD-1/PD-L1 pathway represents a promising strategy to enhance CAR T cell-based cancer immunotherapies.