Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells.

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• NKG2D ligands (NKG2DLs) are widely expressed on cancer cells, presenting a therapeutic target.
• Existing chimeric antigen receptor (CAR) strategies have limitations in targeting NKG2DL-expressing tumors.

Purpose of the Study:

• To develop and evaluate a novel adaptor CAR, termed NKG2D/Dap10-12, for targeting NKG2DLs on cancer cells.
• To assess the efficacy and underlying mechanisms of NKG2D/Dap10-12 CAR T cells in preclinical cancer models.

Main Methods:

• Engineering T cells to co-express NKG2D with a fusion protein comprising Dap10 and a Dap12 endodomain (NKG2D/Dap10-12 CAR).
• Evaluating therapeutic efficacy in established xenograft models with NKG2DL-expressing tumors.
• Conducting structure-function analysis across a panel of CARs to identify key determinants of potency.
• Analyzing cellular metabolism and transcriptomics of engineered T cells.

Main Results:

• NKG2D/Dap10-12 T cells demonstrated compelling efficacy, eradicating or controlling tumors in multiple xenograft models.
• Durable responses, long-term survival, and rejection of tumor re-challenge were achieved.
• Efficacy significantly surpassed that of a clinical-stage NKG2D-CD3ζ CAR.
• Potency was linked to signaling unit proximity, NKG2D expression, adaptor structure, exogenous Dap10, and ITIM number.

Conclusions:

• The NKG2D/Dap10-12 CAR represents a potent new strategy for targeting NKG2DL-expressing cancers.
• Optimized CAR design, including adaptor structure and signaling motifs, is crucial for therapeutic efficacy.
• NKG2D/Dap10-12 CAR T cells exhibit enhanced metabolic fitness and reprogrammed transcription for improved anti-tumor function.