Bispecific T-cell Engagers(BITEs)are a novel form of immunotherapy that overcome a deficiency of immune checkpoint inhibitors(ICI)by targeting a preidentified tumor associated antigen and redirecting a polyclonal popu...Bispecific T-cell Engagers(BITEs)are a novel form of immunotherapy that overcome a deficiency of immune checkpoint inhibitors(ICI)by targeting a preidentified tumor associated antigen and redirecting a polyclonal population of effector T-cells against the tumor.High grade serous ovarian cancer is a lethal disease in the recurrent setting and has not been amenable to ICI therapy.MUC16/CA125 is overexpressed in high grade serous ovarian cancer.BITEs targeting the tumor-retained portion of MUC16/CA125 have recently been described and are in early-phase clinical trials.To identify mechanisms of resistance to BITEs,we collected serum,peripheral blood mononuclear cells,and ascites samples from patients with disease progression on MUC16-directed bispecific antibodies.Analysis of these samples showed downregulation of MUC16/CA125,elevated secretion of VEGF,and epithelial-to-mesenchymal transition in tumor cells.Interestingly,hypoxia was determined to be a driver of these changes.These findings were prospectively validated in ovarian cancer cell lines with CRISPR/Cas9 knockout of MUC16/CA125 and VEGF.Peripheral blood mononuclear cells from patients with disease progression were capable of effective cytolysis ex vivo,suggesting that resistance to therapy was primarily tumor driven.Restoration of MUC16/CA125 expression did not restore cytotoxicity in the presence of increased VEGF secretion.Combination treatment with a VEGF inhibitor rescued cytotoxicity in hypoxia-conditioned ovarian cancer cell lines with preserved target antigen expression.Collectively,these data outline a link between hypoxia and the development of resistance to BITEs and posits inhibition of VEGF inhibition as a potentially important therapeutic intervention.展开更多
基金supported by the Nile Albright Research Foundation(O.O.Y.)The Flatley Foundation(O.O.Y.)+2 种基金The Worden Family Foundation(O.O.Y.)The Barshad Family(O.O.Y.)the Vincent Memorial Hospital Foundation(S.K.B.).
文摘Bispecific T-cell Engagers(BITEs)are a novel form of immunotherapy that overcome a deficiency of immune checkpoint inhibitors(ICI)by targeting a preidentified tumor associated antigen and redirecting a polyclonal population of effector T-cells against the tumor.High grade serous ovarian cancer is a lethal disease in the recurrent setting and has not been amenable to ICI therapy.MUC16/CA125 is overexpressed in high grade serous ovarian cancer.BITEs targeting the tumor-retained portion of MUC16/CA125 have recently been described and are in early-phase clinical trials.To identify mechanisms of resistance to BITEs,we collected serum,peripheral blood mononuclear cells,and ascites samples from patients with disease progression on MUC16-directed bispecific antibodies.Analysis of these samples showed downregulation of MUC16/CA125,elevated secretion of VEGF,and epithelial-to-mesenchymal transition in tumor cells.Interestingly,hypoxia was determined to be a driver of these changes.These findings were prospectively validated in ovarian cancer cell lines with CRISPR/Cas9 knockout of MUC16/CA125 and VEGF.Peripheral blood mononuclear cells from patients with disease progression were capable of effective cytolysis ex vivo,suggesting that resistance to therapy was primarily tumor driven.Restoration of MUC16/CA125 expression did not restore cytotoxicity in the presence of increased VEGF secretion.Combination treatment with a VEGF inhibitor rescued cytotoxicity in hypoxia-conditioned ovarian cancer cell lines with preserved target antigen expression.Collectively,these data outline a link between hypoxia and the development of resistance to BITEs and posits inhibition of VEGF inhibition as a potentially important therapeutic intervention.
