Abstract 5110: Locally administered Interleukin-15 combined with cancer cell-targeted near-infrared photoimmunotherapy in a syngeneic mouse cancer model
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka 
Published: April 2023

Near-infrared photoimmunotherapy (NIR-PIT) is a new anti-cancer treatment by NIR light-induced photochemical reactions within antibody-IRdye700DX conjugates, leading to significant immunogenic cell death. The efficacy of NIR-PIT is synergistically enhanced by combining immune activating agents including immune checkpoint inhibitors and cytokines. However, there are still needs for improving the efficacy of NIR-PIT. A recent study showed that cytokines could exert strong anti-cancer effects when administered locally. Interleukin-15 (IL-15) elicits immune responses that include the generation and persistence of cytotoxic T cells and natural killer (NK) cells. Based on these findings, we hypothesized that local IL-15 administration combined with cancer cell-targeted NIR-PIT could be a highly effective therapy. The efficacy of IL-15 was evaluated by intratumorally or intraperitoneally injecting 5 μg of human IL-15 in C57BL/6 mice inoculated s.c. with murine colon cancer MC38 cells. Human IL-15-secreting MC38 (hIL-15-MC38) was constructed by introducing human IL-15-coding plasmids into MC38 cells and the efficacy of CD44-targeted NIR-PIT was compared in vitro and in vivo. The efficacy of intratumoral IL-15 injection combined with CD44-targeted NIR-PIT was also evaluated in MC38 tumor models. Moreover, bilateral tumor models were used to analyze whether local IL-15 administration combined with CD44-targeted NIT-PIT could induce abscopal effects in untreated tumors. Intratumoral IL-15 injection significantly suppressed tumor growth and induced immune activities compared with intraperitoneal injection. Both hIL-15-MC38 and parental MC38 cells had high CD44 expression on their cell surface and in vitro NIR-PIT induced rapid cell death in both two cell lines. When hIL-15-MC38 or MC38 tumor-bearing mice were treated with or without NIR-PIT, hIL-15-MC38 tumor-bearing mice treated with NIR-PIT showed the best tumor growth inhibition and survival. The hIL-15-MC38 tumors treated with NIR-PIT showed significant increases in the cell number/g tumor of CD8+ T cells, NK cells, and natural killer T cells, and significantly higher Granzyme B expression in these cells compared with the control MC38 tumors. Similar results were observed in vivo by intratumoral IL-15 injection combined with NIR-PIT. Moreover, in bilateral tumor models with right hIL-15-MC38 and left MC38 tumors, NIR-PIT against right hIL-15-MC38 tumors significantly suppressed the growth of left untreated MC38 tumors. In conclusion, local IL-15 administration combined with CD44-targeted NIR-PIT promoted anti-cancer immune responses, resulting in the inhibition of growth of treated tumors, longer survival of mice, and abscopal effects in untreated tumors. Thus, locally administered IL-15 is a promising anti-cancer therapy in combination with cancer cell-targeted NIR-PIT.

Citation Format: Hiroshi Fukushima, Aki Furusawa, Takuya Kato, Seiichiro Takao, Shuhei Okuyama, Peter L. Choyke, Hisataka Kobayashi. Locally administered Interleukin-15 combined with cancer cell-targeted near-infrared photoimmunotherapy in a syngeneic mouse cancer model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5110.