Antitumor activity of a ROR1 × CD3 bispecific antibody in non-small cell lung cancer.

Over the last decade, immuno-oncologic drugs especially CD3-engaging bispecific antibodies (biAbs) are experiencing fast-paced evolution, but big challenges still exist in the clinical development of biAbs in solid tumors, especially non-small cell lung cancer (NSCLC). In this study, we choose a ROR1 × CD3 biAb in scFv-Fc format, named R11 × v9 biAb, to investigate its tumor-inhibiting role in NSCLC. Notably, the ROR1-engaging arm binds both human and mouse ROR1. We found that R11 × v9 biAb specifically binds T cells and tumor cells simultaneously, and dose-dependent cytotoxicity was detected for various ROR1+ NSCLC cell lines. Further, R11 × v9 biAb mediated T-cell derived proinflammatory cytokine secretion, boosted granzyme B and perforin production from CD8+ T cells, and recruited more CD4+ T cells and CD8+ T cells into the tumor tissues. The antitumor activity of R11 × v9 biAb was confirmed in two xenograft mouse models of ROR1+ NSCLC. Importantly, no harmful side effects were observed in these in vivo studies, warranting further preclinical and clinical studies of R11 × v9 biAb in NSCLC.

Dihydroartemisinin and artesunate inhibit aerobic glycolysis via suppressing c-Myc signaling in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of abundant oxygen. Inhibition of aerobic glycolysis remains challenging when identifying potential cancer-specific inhibitors while maintaining or even boosting the anti-cancer immunity. Artemisinin derivatives DHA and AS have shown excellent anti-tumor and immunoenhancing roles in numerous malignancies, but the molecular mechanism of DHA and AS in regulating cancer glucose metabolism is largely unknown. In this study, we proved that DHA and AS inhibit NSCLC growth via prohibiting cancer cell aerobic glycolysis through ERK/c-Myc pathway. First, we proved that DHA and AS have comparable anti-cancer growth roles in both NSCLC cell lines and mouse Lewis Lung Cancer model. Then, our data clearly showed that DHA and AS dose- and time-dependently reduce the uptake of glucose, the production of ATP, and the secretion of lactate, the expression of glucose transporter GLUT1 and two key glycolysis-related enzymes hexokinase and lactate dehydrogenase, as well as the level of c-Myc. Finally, we generated c-Mychigh stable-expressing NSCLC cell line and treated it with DHA or AS, respectively. Our data clearly showed that c-Myc overexpression can partially reverse the glycolysis-repressing role of DHA and AS which strongly supported our proposal that AS and DHA suppress aerobic glycolysis in a c-Myc-dependent manner in NSCLC cells. This study extends our knowledge of artemisinin derivatives in regulating tumor glucose metabolism and provides potential strategy in the therapy of lung cancer.