University of Freiburg Freiburg im Breisgau, Baden
M. Wang1,2, X. Rao3, S. Gaedicke1, L. Wang1,4, B. Menz1, G. Multhoff5, and G. Niedermann3; 1Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany, 2Faculty of Biology, University of Freiburg, Freiburg, Germany, Freiburg, Germany, 3German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany, 4Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China, Harbin, China, 5Klinikum rechts der Isar, Technische Universität München, München, Germany
Purpose/Objective(s):Combination of RT and aPD-1 can result in enhanced efficacy in both local and systemic (abscopal) tumor control, relying on CD8+ T cells. However, many patients do not respond. Fenofibrate (FF) is a PPARa agonist, approved for the management of hypercholesterolemia and hypertriglyceridemia. It has also shown antitumoral effects in preclinical investigations. Our study explores the potential synergistic impact of a triple combination comprising RT, aPD-1, and FF in augmenting both local and systemic tumor control in an abscopal tumor model.Materials/
Methods: Mice harboring bilateral B16-CD133 melanoma tumors were treated with 8 Gy x 3 to the primary tumor. aPD-1 was administered weekly, and FF was administered daily on weekdays for several weeks. Tumor sizes and mouse survival were determined. Tumor-specific CD8+ T cells and tumor-associated high endothelial venules (TA-HEVs) were quantified through flow cytometry (FACS). Results: The therapeutic efficacy of the triple combination markedly surpassed that of all double combinations (n=6 mice/group, p<0.05). Moreover, when CD8+ T cells were depleted with anti-CD8 antibodies, tumor control and survival were not different in triple-treated mice vs. mice treated with the respective double combinations, demonstrating that the triple combination effects depended on CD8+ T cells. In line with this, we found increased numbers of tumor-specific CD8+ T cells in both primary and secondary tumor of triple-treated mice (n=5 mice/group: p<0.05 compared to all respective double-treated groups). Furthermore, the triple combination group showed an increase in TA-HEVs (n=5 mice/group: p<0.05 compared to all respective double-treated groups). Conclusion: Adding FF to hRT+ aPD-1 substantially enhanced control of both primary, irradiated and secondary, non-irradiated tumor depending on CD8+ T cells and correlating with an increase in TA-HEVs, pivotal sites facilitating lymphocyte entry into tumors. We are currently performing further mechanistic experiments to better understand the underlying mechanisms.
