A7: Thermal Ablation Enhances Immunotherapeutic Effect of IP-001 on Orthotopic Liver Cancer in a Rat Model

: Immunosuppression within the tumor microenvironment of hepatocellular carcinoma (HCC) has made immune checkpoints attractive targets for therapy, however they have failed to improve overall survival (OS) as first-line monotherapy compared to sorafenib. Thermal microwave ablation(MWA) has been demonstrated to transiently increase immunogenicity in tumor cells via antigen release, and through combination of IP-001, a specific form of the N‐dihydrogalactochitosan (GC) which sequester ablation‐released tumor antigens and stimulate antigen presenting cells (APCs), a potent Th1 type T cell response can be induced. The aim of this study was to test the immune-activity of IP-001 in combination with MWA of HCC.



Methods: An orthotopic HCC rat model is established by implantation of 2×10^6 N1-S1 cells into the left lobe of liver. When tumor size reached 1.0-1.5 cm^3, the animals were divided randomly into 4 groups, 1) MWA + IP-001; 2) MWA + saline; 3) sham MWA + IP-001 and 4) sham MWA + saline (n=5 in each group). For IP-001 and MWA administration, 0.4 ml/kg(4mg) IP-001 was injected into adjacent tissue 1.5 cm around tumor, and tumor thermal ablation was performed by microwave (MWA) at 25 W and temperature measured at 55 °C.


Results:

A significant increase in infiltration of inflammatory/immune cells were found in the tumor adjacent tissues of MWA + IP-001 mice, in comparison to the other 3 groups. The Flow cytometry results indicated that there were significant increases of cytotoxic T cells (CD8⁺), macrophages (CD11b⁺), dendritic cells (CD11b⁺CD103⁺) and NK cells (CD161⁺) in the combination of MWA and IP001 treated mice, compared to other 3 groups(Figure). There was similar upregulation in interferon gamma cells across all three treatment groups when compared to saline. There was a significant improvement(3 fold increase) in T helper cells in the combined microwave ablation and IP001 when compared to IP001 alone.



Conclusions: A combination of IP-001 and MWA in an HCC Murine model led to significant increase in macrophages (CD11b
⁺

cells) dendritic cells (CD11b
⁺

CD 103
⁺

cells), NK cells (CD 161
⁺

cells), significant upregulation of interferon gamma, and improvement in T helper cells.