Enhancing CAR- and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Cancer antigen heterogeneity limits engineered T-cell therapy efficacy.
• Antigen escape is a key mechanism of treatment resistance.

Purpose of the Study:

• To develop a novel strategy to enhance T-cell recognition and lysis of tumors with suboptimal antigen expression.
• To engineer a synapse-stabilizing receptor (SSR) that boosts cytotoxic signaling and immune synapse formation.

Main Methods:

• Designed an SSR with a modified linker for activation of T cells (LAT) endodomain to amplify CD3ζ signaling.
• Investigated SSR function in acute myeloid leukemia models using chimeric antigen receptors (CARs) and T cell receptors (TCRs).
• Assessed SSR-mediated cytotoxicity against cancer cells and normal tissues.

Main Results:

• The SSR amplifies T-cell signaling, leading to enhanced Ca2+ flux, MAPK/NF-kB activation, and T-cell degranulation.
• A modified LAT endodomain (LAT177) was identified to minimize SSR-mediated cytotoxicity.
• CD38-targeting SSR enhanced lysis of antigen-low cancer cells in combination with CLL1-specific CAR and survivin-specific TCR.
• SSR demonstrated selectivity, avoiding significant cytotoxicity against normal CD38+ tissues.

Conclusions:

• SSR arming enhances targeting of antigenically heterogeneous cancers.
• This strategy improves the safety and selectivity of therapeutic T cells.
• SSR represents a promising approach to overcome treatment resistance in engineered T-cell therapies.