3126 - Rutherrin^® Activated by Radiation Therapy Induces Synergistic Tumor Regression through Direct Destruction and Immune Activation in Multiple Preclinical Cancer Models

Purpose/Objective(s): This abstract evaluates Rutherrin^® in RDT, assessing tumor regression, survival, and immune response activation across preclinical GlioBlastoma Multiforme (“GBM”), colorectal, lung, and lymphoma models.

Materials/Methods: In vitro, Rutherrin^® RDT was tested in multiple cancer cell lines, measuring viability, ROS production, immune modulation, and drug efflux rate. In vivo, subcutaneous (“SQ”) (colorectal, lung, lymphoma) and orthotopic (GBM, lung) tumor models were used. Preferential uptake, pharmacodynamics and treatment response were analyzed. Mice received IV Rutherrin® with fractionated RT, assessing tumor growth, survival, and immune response.

Results: In vitro, RDT with Rutherrin^® induced a significant 2-log increase in cancer cell kill versus RT alone. ROS production increased significantly, suggesting oxidative stress as a key component of cytotoxicity. Rutherrin^® modulated drug efflux pathways, counteracting multidrug and radiation resistance. Immune-related chemokine and cytokine expression increased, indicating a secondary immune response.

In vivo, Rutherrin^® + RT versus RT alone significantly enhanced complete tumor regression in the SQ colorectal model, with Rutherrin®-treated mice exhibiting long-term resistance to tumor rechallenge, indicating robust immune memory formation. Similar outcomes were observed in lung and lymphoma models. In GBM, Rutherrin® crossed the blood-brain barrier, showing >10-fold preferential tumor uptake. In the orthotopic lung model, dose-dependent lung uptake was observed, with increasing tumor selectivity over time. In both GBM and lung models, Rutherrin^® + RT significantly delayed tumor growth and prolonged survival over RT alone.

Conclusion: Rutherrin^® activated by RT enhanced tumor regression, immune memory response, and overcame resistance mechanisms versus RT alone. By enhancing ROS-mediated cytotoxicity and modulating drug efflux, Rutherrin^® presents a powerful approach to improve local tumor control and systemic immunity. These findings support clinical investigation of Rutherrin^® as a transformative adjunct to RT for improved cancer treatment.