Significantly increased anti-tumor activity of carcinoembryonic antigen-specific chimeric antigen receptor T cells in combination with recombinant human IL-12.

ABSTRACT

BACKGROUND AIMS: Chimeric antigen receptor T cells (CAR-T cells) have been successfully used in treatments of hematological tumors, however, their anti-tumor activity in solid tumor treatments was limited. As IL-12 increases T-cell immune functions, we designed carcinoembryonic antigen (CEA) specific CAR-T (CEA-CAR-T) cells and, for the first time, used them in combination with recombinant human IL-12 (rhIL-12) to treat several types of solid tumors. METHODS: In vitro anti-tumor activity of CEA-CAR-T cells in combination with rhIL-12 was confirmed by evaluation of CEA-CAR-T cell activation, proliferation, and cytotoxicity after co-incubation with CEA-positive or CEA-negative human tumor cells. In vivo anti-tumor activity of CEA-CAR-T cells in combination with rhIL-12 was confirmed in a xenograft model in nude mice for treatments of several types of solid tumors. RESULTS: In vitro experiments confirmed that rhIL-12 significantly increased the activation, proliferation, and cytotoxicity of CEA-CAR-T cells. Similarly, in vivo experiments found that CEA-CAR-T cells in combination with rhIL-12 had significantly enhanced anti-tumor activity than CEA-CAR-T cells in growth inhibition of newly colonized colorectal cancer cell HT-29, pancreatic cancer cell AsPC-1, and gastric cancer cell MGC803. CONCLUSIONS: These works confirmed that simultaneous use of cytokines, for example, rhIL-12, can increase the anti-tumor activity of CAR-T cells, especially for treatments of several types of solid tumors.