Journal Article

Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B‐NIT)

Matsushita, Hirokazu, Kondo, Natsuko, Togashi, Yosuke, Yamasaki, Osamu, Fujimoto, Takuya, Kenmotsu, Naoya, Fujimura, Atsushi, Fujiwara, Toshiyoshi, Kitamatsu, Mizuki, Michiue, Hiroyuki, Mizuta, Ryo, Shirakawa, Makoto, Suzuki, Minoru, Sakurai, Yoshinori, Otani, Yoshihiro, Teraishi, Fuminori, Kanehira, Noriyuki, Takata, Takushi, Shigeyasu, Kunitoshi, Igawa, Kazuyo

2024

Overview

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B‐NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy‐resistant advanced‐stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti‐PD‐1 antibody immunotherapy group did not show tumor suppression. Only the B‐NIT group showed strong tumor growth inhibition at both BNCT‐treated and shielded distant sites. Intratumoral CD8+ T‐cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B‐NIT group. Analysis of CD8+ T cells in tumor‐infiltrating lymphocytes (TILs) showed that CD62L‐ CD44+ effector memory T cells and CD69+ early‐activated T cells were predominantly increased in the B‐NIT group. Administration of CD8‐depleting mAb to the B‐NIT group completely suppressed the augmented therapeutic effects. This indicated that B‐NIT has a potent immune‐induced abscopal effect, directly destroying tumors with BNCT, inducing antigen‐spreading effects, and protecting normal tissue. B‐NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy‐resistant malignancies, B‐NIT can become a new treatment candidate for advanced‐stage cancers. Boron neutron capture therapy leads to new treatment option to overcome cancer immunotherapy resistance.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: abscopal effect / advanced melanoma / Amino acids / Animals / Antibodies / Biosynthesis / Boron / boron neutron capture therapy / Boron Neutron Capture Therapy - methods / boron‐neutron immunotherapy / Brain cancer / Cancer therapies / CD44 antigen / CD69 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell death / Cell Line, Tumor / Chemoradiotherapy / Combination therapy / Combined Modality Therapy / Drug dosages / Drug resistance / Drug Resistance, Neoplasm / Effector cells / Female / Genomics / Head & neck cancer / HMGB1 protein / HMGB1 Protein - metabolism / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / immune combination therapy / Immunohistochemistry / Immunological memory / Immunosuppressive agents / Immunotherapy / Immunotherapy - methods / L-selectin / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Malignancy / Medical prognosis / Melanoma / Melanoma, Experimental - immunology / Melanoma, Experimental - therapy / Memory cells / Metastases / Mice / Mice, Inbred C57BL / Monoclonal antibodies / Neutron radiation / Neutrons / Original / ORIGINAL ARTICLE / Skin cancer / Statistical analysis / Tumor suppression / Tumors / Variance analysis / White people