The Future of Combining Carbon-Ion Radiotherapy with Immunotherapy: Evidence and Progress in Mouse Models

Abstract

After >60 years since the first treatment, particle radiation therapy (RT) is now used to treat various types of tumors worldwide. Particle RT results in favorable outcomes, especially in local control, because of its biological properties and excellent dose distribution. However, similar to other types of cancer treatment, metastasis control is a crucial issue. Notably, immunotherapy is used for cancer treatment with high risk for recurrence and/or metastasis. These 2 cancer therapies could be ideal, complementary partners for noninvasive cancer treatment. In this review, we will focus on preclinical studies combining particle RT, especially carbon ion RT, and immunotherapy.

Keywords: dendritic cell; carbon-ion; immunotherapy; mouse; radiotherapy.

Figure 1.

Radiation-induced immune activation and combination with immunotherapy. Radiation therapy is able to induce cancer cell death, including immunogenic cell death. The dying cells act as a source of tumor antigen to antigen-presenting cells, such as dendritic cells and macrophages. Mature antigen-presenting cells display tumor antigens combined with major histocompatibility complexes and stimulate T cells to become cytotoxic T cells. The activated cytotoxic T cells are expected to attack cancer, including micrometastases and circulating tumor cells. If we find ways to control the mechanisms in any patients, radiation therapy is able to use an inducer of in situ vaccine. For immunotherapy, these key factors, such as immune cells and cytokines, are used for the treatment. Therefore, combination immunotherapy–radiation therapy is expected to enhance the antitumor effects.

Figure 2.

Types of evaluation for effectiveness of radiation therapy–induced immune response. If irradiation induces antitumor immune response in the tumor-bearing mouse, evaluation of activation is possible by the following methods: rejection—evaluate rejection rate of secondary tumor inoculation after treatment of the first tumor; metastasis suppression—evaluate number of metastases after treatment; and abscopal effect—evaluate nonirradiated tumor growth after irradiation of another tumor.

Figure 3.

The possible mechanisms of metastasis reduction. High-dose irradiation is able to suppress the growth of the irradiated tumor, and distant lung metastasis may also be inhibited. However, it is difficult to evaluate whether the inhibition of metastasis results from immune response or is a consequence of primary tumor regression. In contrast, low-dose irradiation has less effect on tumor growth. The irradiated tumor is able to sustain growth. If lung metastasis is inhibited significantly in this condition, it might indicate a direct effect of carbon-ion radiation therapy in metastases. Moreover, the radiation-induced immune response may be evaluated.