Colorectal cancer (CRC) metastases to the liver (CRC-LiMets) represent a major clinical challenge because of their poor response to conventional therapies. Adoptive cell therapy (ACT) with tumor redirected T cells holds promise for cancer treatment; yet difficult T-cell trafficking into solid tumor tissues and suppressive cues generated in the tumor microenvironment (TME) of hepatic metastases can hinder their efficacy. CD1d-restricted invariant Natural Killer T (iNKT) cells offer a unique therapeutic opportunity due to their ability to simultaneously kill malignant cells and modulate the TME by limiting tumor-supportive myeloid populations.
In this study, we have engineered iNKT cells with a proof-of-concept CAR specific for the human carcinoembryonic antigen (hCEA), a clinically relevant CRC target. In preclinical models of liver metastases, generated by syngeneic hCEA-expressing mouse CRC tumor orthotopic injection in hCEA transgenic mice, we observed that CAR-iNKT cells effectively homed to the liver and eradicated not only small lesions but also established, large metastatic tumors—highlighting their superior efficacy compared to conventional CAR-T cells. To characterize iNKT cell behavior within human tumor contexts and validate their therapeutic potential, we are currently assessing the anti-tumor activity of CAR-redirected human iNKT cells in humanized NSG mice bearing human CRC liver metastases and reconstituted human myeloid compartment.
This study will help define efficacy and safety of tumor redirected iNKT cells for the treatment CRC liver metastases, paving the way for translational development toward clinical application in cancer patients.