Description
Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and no effective treatment. Our previous study showed that the combination therapy of an immune checkpoint inhibitor, anti-CTLA-4 antibody (C4), and high-dose photon (16 Gy or 8 Gy x 3 fractions) and carbon-ion (C-ion) irradiation (8.2 Gy or 4.1 Gy x 3 fractions) shrank not only irradiated tumor but also unirradiated tumor, which is known as the abscopal effect. C-ion irradiation has some physical advantages, including Bragg-peak, enabling highly conformal dose to tumors and stronger cell killing effect than photon irradiation. Nevertheless, due to the proximity of risk organs such as stomach and duodenum around pancreas, dose reduction is preferred, provided that it can achieve comparative tumor control and abscopal effect. We therefore investigated whether combination therapy of C4 and medium-dose of C-ion irradiation induces the abscopal effect, along with changes in tumor microenvironment (TME). C-ion irradiation was conducted at the National Institutes for Quantum Science. C57BL/6 mice inoculated murine PDAC cells at both legs were irradiated to only one leg. The mice were assigned to the following groups: C4, 5.1 Gy+C4, and 2.1 Gy x 3 fractions+C4 groups. The doses of 5.1 Gy and 2.1 Gy x 3 fractions were found to be the biological equivalent dose to 10 Gy with photon irradiation based on our experimental data. All mice were administered with C4 intraperitoneally 3 times every 3 days. Half of mice in 5.1 Gy+C4 group experienced only local control, whereas half of those mice exhibited both local control and abscopal effect. Interestingly, six of seven mice in 2.1 Gy x 3 fractions+C4 group experienced both local control and abscopal effect, while one of seven mice experienced only local control. Compared to 5.1 Gy+C4 group, the proportion of cytotoxic T lymphocytes (CTL) was significantly increased in 2.1 Gy x 3 fractions+C4 group for both irradiated and unirradiated tumors, leading to the increased CTL/regulatory T cells (Treg) ratio at 5 days after the final treatment. These results suggest that not single but fractioned irradiation with C4 contributes to the induction of the abscopal effect and improvements of TME even at lower doses with C-ion than photon irradiation. We are currently developing an experimental system that replicates the unique microenvironment of PDAC, including stroma and cancer associated fibroblasts. This aspect will be further discussed in the presentation. The author is grateful to F-REI (JPFR24040302) for the support of travel expenses.
