2942 - Toward a Clinical Trial in the Human Liver: Effect of Intralesional Diffusing Alpha Emitters Radiation Therapy on Orthotopic Murine Liver Colorectal Metastasis Growth, Healthy Liver Tissue and Immune
O. Zlotnik1, A. Kapelanski-Lamoureux2, A. Tsatoumas2, A. Gantz2, J. Kalil1, S. Petrillo2, R. Segal3, A. Lazaris4, V. Domankevich-Bachar5, and P. Metrakos1; 1McGill University Health Center, Montreal, QC, Canada, 2McGill University, Montreal, QC, Canada, 3Alpha Tau Medical, Jerusalem, Israel, 4McGill Univesity, Montreal, QC, Canada, 5Alpha Tau, Jerusalem, Israel
Purpose/Objective(s): Alpha DaRT is a Raduim-224-loaded source that disperse alpha particles in the tumor microenvironment, thereby creating a “killing zone” of several millimeters in diameter. The treatment was previously shown very high response rates in skin and head and neck SCC patients. However, its implementation in the metastatic setting of an internal organ, such as the liver, was not yet established. In this study we evaluated the feasibility of Alpha DaRT in treating a liver colorectal metastasis. We hypothesised that a single Alpha DaRT source will delay the growth of a single liver lesion, without affecting untreated healthy liver tissue, due to the radiation short range. In addition, we postulated that the treatment would lead to an immune-supportive microenvironment in the liver. Materials/
Methods: MC38 colorectal cancer liver metastases model was modified to allow Alpha DaRT treatment, while preserving the spleen for an intact immune system. Liver tumor tissue from C57BL/6 mice, which were previously spleenically injected with MC38 cells, were first harvested. Then, a single tumor tissue piece was orthotopically implanted into the liver of naïve mice and allowed to grow. After MRI imaging of the tumor, either active or inert Alpha DaRT source was implanted in the tumor core. Following treatment, liver tissue was subjected to hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining. Results: Results showed a significant growth delay in liver tumors treated with active Alpha DaRT compared to liver tumors who underwent inert source implantation. H&E staining showed that, unlike conventional radiation therapies, the treatment preserved healthy liver tissue adjacent to the tumor. F4/80+ macrophages were significantly lower at the tumor/normal interface in the radioactive treatment arm compared to control. Conclusion: These findings provide an important preclinical support for the potential feasibility of treating internal organ cancers with Alpha DaRT, paving the way for further clinical investigation. In addition, the study suggests the safety advantage of the treatment for surrounding healthy tissues, and reduction of immune suppressive cell population in the liver tumor that may support future combinations with immunotherapy.
