Although the outcome of patients with Hodgkin lymphoma (HL) is comparably high, it worsens rapidly in relapsed or refractory disease. In the pursuit of improving cancer treatment and finding new therapy options, repurposing drugs has evolved as a promising strategy. This project takes a systematic look at the direct antitumor effect of 12 non-oncological, repurposed drugs in HL that survived initial screening in a broad panel of cell lines. Additionally, we consider their immunological effects and aim to decipher strategies on how to potentially use them in conjunction with immunotherapy.
Luciferase toxicity assays in different concentrations were performed with four HL cell lines, narrowing down the list of 12 to the five most toxic agents which were then tested again in three different combinations. The most effective combination was then evaluated in mouse models. To evaluate the influence of the screening survivor drugs on immune response, assays for T-cell activation, macrophage polarization and phagocytosis were conducted.
Five compounds, Albendazole (Alb), Auranofin (Aur), Disulfiram (Dis), Fluvastatin (Flu) and Propranolol (Pro) showed markedly elevated in-vitro toxicity. The three combinations Alb+Aur+Dis+Pro, Aur+Dis+Flu+Pro and a combination of all 5 drugs showed synergistic cytotoxicity in HL cell lines. Latter combination clearly reduced tumor growth in mouse models. Except for Doxycycline, which markedly repressed T-cell activation, none of the other tested 11 compounds showed negative effects on either T-cell activation, or macrophage polarization and phagocytosis. On the contrary, Eprosartan (Epro), Metformin (Met), Clofibrate (Clof) and Ornidazole (Orni) increased antibody dependent cellular phagocytosis (ADCP) in in-vitro assays.
This project shows that combinations of repurposed, non-oncological drugs at safe doses have a direct cytotoxic effect against HL and a potentially beneficial impact on key immune response mechanisms. Taken together, our results justify further evaluation of combinations of these clinically known drugs with chemotherapy or checkpoint blockade in cases of HL without other treatment options.
Mia Lohmann, Iris Buchberger, Anna Beielstein, Başak Kaçar, Julia Mattlener, Marieke Nill, Zhiyuan Shi, Jan-Michel Heger, Christian Pallasch, Roland Ullrich, Sven Borchmann