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It has been demonstrated that aggressive in situ tumor destruction (ablation) could lead to the release of tumor antigens, which can stimulate anti-tumor immune responses. We developed an innovative method of tumor ablation based on intratumoral alpha-irradiation, diffusing alpha-emitters radiation therapy (DaRT), which efficiently ablates local tumors and enhances anti-tumor immunity. In this study, we investigated the anti-tumor potency of a treatment strategy, which combines DaRT tumor ablation with two approaches for the enhancement of anti-tumor reactivity: (1) neutralization of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and (2) boost the immune response by the immunoadjuvant CpG. Mice bearing DA3 mammary adenocarcinoma with metastases were treated with DaRT wires in combination with a MDSC inhibitor (sildenafil), Treg inhibitor (cyclophosphamide at low dose), and the immunostimulant, CpG. Combination of all four therapies led to a complete rejection of primary tumors (in 3 out of 20 tumor-bearing mice) and to the elimination of lung metastases. The treatment with DaRT and Treg or MDSC inhibitors (without CpG) also resulted in a significant reduction in tumor size, reduced the lung metastatic burden, and extended survival compared to the corresponding controls. We suggest that the therapy with DaRT combined with the inhibition of immunosuppressive cells and CpG reinforced both local and systemic anti-tumor immune responses and displayed a significant anti-tumor effect in tumor-bearing mice.

Purpose: We developed (224)Ra-loaded wires, which release by recoil alpha emitting nuclei into solid tumors and cause tumor cell killing. This research examined if the major damage was inflicted by alpha particles emitted from these atoms or by direct gamma and beta emissions from the inserted wires. We also examined the efficacy of this treatment against colon cancer in combination with chemotherapy., Materials and Methods: Mouse colon carcinomas (CT-26 xenografts), treated by intra-tumoral radioactive wires loaded with (224)Ra atoms were monitored for effects on tumor growth, intratumoral tissue damage and distribution of alpha emitting atoms. The effects were compared with those of (224)Ra-loaded wires coated with poly methyl methacrylate (PMMA), which blocks atom recoil. Similar experiments were performed with radioactive wires combined with systemic 5-FU., Results: (224)Ra-loaded wires inhibited tumor growth and formed necrotic areas inside the tumor. PMMA coated wires did not inhibit tumor growth, and caused minor intratumoral damage. Autoradiography images of tumors treated with (224)Ra-loaded wires revealed a spread of alpha emitters over several mm, whereas PMMA-coated wires showed no such spread. Injection of 5-FU with (224)Ra-loaded wires augmented tumor growth retardation and cure., Conclusions: (224)Ra-loaded wires ablate solid tumors by the release of alpha-particle emitting atoms inside the tissue, an effect that can be enhanced by combining this method with chemotherapy.