DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against...

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR) T cell therapies are effective against hematological malignancies but require new targets for broader application.
• There is a need for CARs capable of targeting non-hematological malignancies and multiple tumor types.

Purpose of the Study:

• To engineer and evaluate novel CARs based on the natural killer cell receptor DNAM-1 for targeting a range of cancers.
• To assess the efficacy of DNAM-1 CARs against tumors expressing DNAM-1 ligands PVR and nectin-2.

Main Methods:

• Designed CARs utilizing the tumor recognition ability of DNAM-1.
• Assessed DNAM-1 CARs' tumor cell cytotoxicity and interferon-gamma (IFN-γ) secretion in vitro.
• Evaluated the impact of co-stimulatory domains on DNAM-1 CAR expression and function.
• Tested a DNAM-1/CD3zeta CAR in a murine melanoma model for in vivo efficacy.

Main Results:

• DNAM-1 CARs demonstrated high tumor cell cytotoxicity against targets expressing PVR and nectin-2.
• IFN-γ secretion was low in vitro, and co-stimulatory domains did not enhance DNAM-1 CAR performance.
• A DNAM-1/CD3zeta CAR significantly reduced tumor burden in a preclinical melanoma model.

Conclusions:

• DNAM-1-based CARs represent a potential therapeutic strategy for hematological and solid tumors expressing PVR and nectin-2.
• These CARs offer a novel approach for targeting multiple cancer types by leveraging the DNAM-1 pathway.