Efficient Treatment of Mouse Breast Adenocarcinoma by Ablation with Intratumoral Alpha Irradiation Combined with Inhibitors of Immunosuppressor Cells and Immunostimulation with CpG - ICMS2015 Abstract Submission Form Tumor Microenvironment Conference

Margalit Efrati ¹ Hila Confino ¹ Michael Schmidt ² Ilan Hochman ¹ Viktor Umansky ³ Itzhak Kelson ² Yona Keisari ¹

¹Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Israel
²Department of Physics and Astronomy, Sackler Faculty of Exact sciences, Tel Aviv University, Israel
³Skin Cancer Unit, German Cancer Research Center, Heidelberg and Department of Dermatology, Venereology and Allergology, Ruprecht-Karl University of Heidelberg, Germany

Background: Our team developed a potent tumor ablation technique, Diffusing Alpha-emitters Radiation Therapy (DaRT), which is based on insertion of ²²⁴Ra–loaded wire(s) into the tumor. Short-lived atoms are released from the wires, spread in the tumor and emit lethal alpha particles, which kill the malignant cells. The destruction provoked T cell dependent anti-tumor immune reactions, which conferred protection against a tumor challenge, and killed malignant cells in the primary tumor and distant metastases.

In this study we attempted to enforce the anti-tumor immune reaction by combining DaRT with neutralization of immunosuppressive regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs), and immunostimulation by the immunoadjuvant CpG.

Results: Mice bearing DA3 mammary adenocarcinoma with metastases were treated with DaRT wires in combination with an MDSC inhibitor (sildenafil), a Tregs inhibitor (low dose cyclophosphamide), and the immunostimulant, CpG. Combination of DaRT with the three immunomodulating agents resulted in tumor growth retardation, complete rejection of primary tumors (1/9 tumor-bearing mice) and retardation of lung metastases. Only 30% of such treated animals carried lung metastases compared with over 50% of the mice treated with an inert wire and the three reagents. Treatment with DaRT, Treg and MDSC inhibitors (without CpG) also diminished significantly tumor growth and reduced the lung metastatic burden. In 60% of such treated mice lung metastases were detected compared to 77% of the animals treated by a non-radioactive wire and the inhibitors.

Conclusions: Therapy with DaRT combined with the inhibition of immunosuppressive cells and immunostimulation with CpG enforced both local and systemic anti-tumor immune responses. This treatment can be applied in patients when surgery is not an option or before surgical removal of tumors.