Targeting Multiple Tumors Using T-Cells Engineered to Express a Natural Cytotoxicity Receptor 2-Based Chimeric...

Area of Science:

• Immunology
• Oncology
• Cellular Therapy

Background:

• Immunotherapy, particularly adoptive T-cell transfer, shows promise for cancer treatment.
• Chimeric antigen receptor (CAR)-T cells are effective against hematological malignancies but limited for solid tumors.
• Natural killer (NK) cells possess anti-tumor functions but face challenges in expansion and overcoming inhibitory mechanisms.

Purpose of the Study:

• To engineer T-cells with NK cell recognition capabilities for improved solid tumor targeting.
• To investigate the efficacy of a novel NCR2-based CAR in T-cells for non-MHC restricted tumor recognition.
• To enhance cancer immunotherapy by combining NK cell recognition with T-cell effector functions.

Main Methods:

• Genetic modification of human T-cells with chimeric receptors based on the human NCR2 molecule.
• Assessment of engineered T-cells' antitumor activity both in vitro and in vivo.
• Evaluation of tumor recognition and cytotoxicity mediated by the novel CAR in a mouse model.

Main Results:

• Expression of the NCR2-derived CAR (s4428z) in primary lymphocytes conferred T-cells with specific tumor recognition.
• Engineered T-cells demonstrated significant tumor cytotoxicity in a preclinical mouse model.
• The s4428z CAR enabled T-cells to recognize heterogeneous tumors in a non-MHC restricted manner.

Conclusions:

• Combining NK cell recognition mechanisms with T-cell effector functions represents a promising strategy for cancer immunotherapy.
• NCR2-based CARs offer a novel approach to enhance T-cell targeting of solid tumors.
• This study validates the potential of engineered T-cells with NK cell properties for improved cancer treatment outcomes.