Purpose: Cancer immunotherapy is an attractive therapy in terms of cancer cell specificity. In the most of cancer patients, cancer immune responses are suppressed in tumor tissue by regulatory T lymphocytes and suppressing signals such as PD-1/PD-L1. Unfortunately, cancer immunotherapies are not so effective. To improve this problem, immuno-checkpoint inhibitors were developed and could prolong the survival time. However, this effect is not enough. It is necessary to develop new approach to enhance cancer immune response and combine with immuno-checkpoint inhibitors. Recently, it is reported that radiotherapy, photodynamic therapy and high intensity focused ultrasound therapy have potency to induce cancer immune response.In addition, it was suggested that ultrasound contrast agents such as microbubbles combined with therapeutic ultrasound would be useful for drug and gene delivery. On the other hand, there is no report about the immune response by the combination of ultrasound contrast imaging agent and non-focused ultrasound. In this study, we assessed the tumor growth suppression and the induction of cellular immune response by the combination of our lipid based bubble and non-focused ultrasound.
Methods: Colon-26 cells (mouse colon carcinoma) were inoculated into the back of mice. After 8 days, our bubbles were intratumorally injected and ultrasound (Frequency: 1 MHz, Intensity: 0-4 W/cm2, Duty: 50%, Burst rate: 2Hz, Time: 2 min) was transdermally exposed toward tumor tissue. The anti-tumor effect was evaluated by measuring tumor volume. To assess the effect of cellular immunity on tumor growth suppression, we also examined in CD8 positive T cells depleted mice by injection of anti-CD8 antibody.
Results: In the combination of lipid based bubble and lower intensity (1-3 W/cm2) of non-focused ultrasound, tumor growth suppression was not observed. On the other hand, in the treatment of lipid based bubble and non-focused ultrasound (4 W/cm2), tumor growth was effectively suppressed. In addition, this tumor growth suppression was cancelled in the CD8 positive T cell depleted mice. From these results, the combination therapy of lipid based bubble and non-focused ultrasound would be an effective cancer therapy based on priming the cellular immune response.
Conclusion: This combination therapy might be a novel cancer immunotherapy based on changing the immunological microenvironment in tumor tissue.
Daiki Omata– Dr., Faculty of Pharma-Science, Teikyo University, Tokyo, Tokyo, Japan
Lisa Munakata– B.A., Teikyo University, Itabashi-ku, Tokyo, Japan
Tadamitsu Shima– Faculty of Pharma-Science, Teikyo University, Itabashi-ku, Tokyo, Japan
Yuno Suzuki– Itabashi-ku, Tokyo, Japan
Saori Kageyama– Faculty of Pharma-Science, Teikyo University, Itabashi-ku, Tokyo, Japan
Fumiko Hagiwara– Itabashi-ku, Tokyo, Japan
Kazuo Maruyama– Faculty of Pharma-Science, Teikyo University, Itabashi-ku, Tokyo, Japan