Next-Generation CEA-CAR-NK-92 Cells against Solid Tumors: Overcoming Tumor Microenvironment Challenges in Colorectal...

Area of Science:

• Immunotherapy
• Oncology
• Cell Therapy

Background:

• Colorectal carcinoma (CRC) poses a significant therapeutic challenge, necessitating advanced treatment modalities.
• Chimeric antigen receptor (CAR) natural killer (NK) cell therapy is an emerging alternative to CAR T-cell therapy.
• Carcinoembryonic antigen (CEA) is a promising target for CRC, but its shedding complicates therapy.

Purpose of the Study:

• To develop and evaluate a next-generation CAR construct targeting cell-associated CEA on colorectal cancer cells.
• To enhance CAR-NK cell homing, infiltration, and efficacy within the tumor microenvironment (TME).
• To assess the safety and specificity of the engineered CAR-NK-92 cell line, particularly regarding fratricide.

Main Methods:

• Development of a novel CAR construct targeting cell-associated CEA, incorporating PD1 and CCR4.
• Utilizing 3D multicellular tumor spheroid (MCTS) models to simulate the CRC TME.
• Evaluation of CEA-CAR-NK-92 cell cytotoxicity, homing capabilities, and fratricide in vitro.

Main Results:

• CEA-CAR-NK-92 cells exhibited significant cytotoxicity against CRC cell lines and MCTS models.
• The CCR4 receptor enhanced CAR-NK cell homing towards CCL17 and CCL22 ligands.
• The CAR design effectively prevented trogocytosis-induced fratricide, indicating improved safety.

Conclusions:

• Engineered CEA-CAR-NK-92 cell therapy shows promise as a precise and effective treatment for colorectal carcinoma.
• The incorporation of a PD1-checkpoint inhibitor and CCR4 receptor enhances therapeutic potential.
• This approach offers a viable strategy to overcome challenges associated with CEA shedding and TME infiltration.