Modular delivery of co-stimulatory signals through a PD-1-based immunoswitch receptor improves the functionality of Hepatitis B Virus-specific engineered T cells

To develop PD-1–based immunoswitch receptors that convert PD-L1 engagement into co-stimulation to enhance T-cell responses against HBV.

Immunoswitch Receptor Design: Engineered PD-1 immunoswitch receptors were linked to intracellular CD28, 4-1BB, or OX40 signaling domains and expressed in HBV-specific CAR- and TCR-engineered T cells.
Assessment of T-cell Activity: T-cell functionality was evaluated through antigen- and PD-L1-dependent co-cultures, transcription factor reporter systems, and an HBV carrier mouse model.

Signal stacking of additional co-stimulatory domains did not improve functionality of second-generation S-CAR.
Modular delivery of co-stimulation via PD-1-based immunoswitch receptors enhanced T-cell antigen sensitivity, functionality, and cytotoxicity.
PD-L1 supplied in trans supported on-target functionality of engineered T cells.
PD-1_4-1BB induced sustained NF-κB signaling and reduced exhaustion-associated pathways.
In vivo, PD-1_4-1BB improved T-cell persistence and decreased TOX upregulation.

PD-1–based immunoswitch receptors provide a modular strategy to enhance engineered T-cell responses against HBV.

The study does not address long-term effects of PD-1 immunoswitch receptors in human subjects.
Potential variability in responses among different patient populations was not explored.

PD-1–based immunoswitch receptors represent a platform for improving adoptive T-cell therapies in chronic infections and cancer.