2299P - Mebendazole enhances the anticancer effect of irinotecan and check-point inhibitor in vitro and in vivo

Background

Mebendazole (Mbz), a well-known anthelminthic drug, has been demonstrated to have anti-cancer properties in tumor models and patients. The therapeutic effect of Mbz was suggested to be due to microtubule inhibition, but more recently we reported that Mbz switches macrophages from the M2 to the tumor suppressive M1 phenotype. The aims of this study were to further investigate in tumor models the cytotoxic and immunomodulatory effects of Mbz alone, in combination with cytotoxic drugs and PD-1 antibody.

Methods

Tumor samples from patients with solid or hematological malignancies undergoing diagnostic or therapeutic procedures were obtained in accordance with ethical permission. The samples were then prepared to isolated tumor cells for ex vivo testing. Ex vivo activity of Mbz alone and in combination with standard cytotoxic drugs was assessed using the fluorometric microculture cytotoxic assay. Survival index and synergy scores were calculated using GraphPad and SynergyFinder. In vivo antitumor activity of Mbz, irinotecan, a PD-1 inhibitor and their combinations were examined in a murine BALB/c model with inoculated syngeneic colon cancer cells (CT26). Tumor growth was measured by caliper and tumors were retrieved and assessed by flow cytometry for immune cell infiltration.

Results

Mbz alone showed some modest cytotoxic activity against patient tumor cells ex vivo, with hematological tumor cells being slightly more sensitive. The cytotoxic effect of Mbz was generally additive to that of other drugs but synergistic when combined with irinotecan. In the murine model, Mbz, irinotecan and the PD-1 antibody alone inhibited tumor growth. Combined with irinotecan Mbz had an additive effect, but was synergistic when combined with the PD-1 antibody. In line with the latter observation, flow cytometry showed an increase of M1 macrophages and decrease of M2 macrophages in tumors from animals treated with the combination.

Conclusions

Mbz show promising features making it suitable for repositioning into an anti-cancer drug, most notably as a modulator of the macrophage phenotype that may enhance and the effect of check-point inhibitors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Sharmineh Mansoori.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.