Inhibition of MDR1 overcomes resistance to brentuximab vedotin in Hodgkin lymphoma

Purpose: In classical Hodgkin lymphoma (HL), the malignant Reed-Sternberg cells express the cell surface marker CD30. Brentuximab vedotin (BV) is an antibody-drug conjugate that selectively delivers a potent cytotoxic agent, monomethyl auristatin E (MMAE), to CD30-positive cells. Although BV elicits a high response rate (75%) in relapsed/refractory HL, most patients who respond to BV eventually develop resistance. Experimental Design: We developed two BV-resistant HL cell line models using a pulsatile approach and observed that resistance to BV is associated with an upregulation of multidrug resistance-1 (MDR1). We then conducted a phase 1 trial combining BV and cyclosporine A (CsA) in patients with relapsed/refractory HL. Results: Here, we show that competitive inhibition of MDR1 restored sensitivity to BV in our BV-resistant cell lines by increasing intracellular MMAE levels, and potentiated BV activity in BV-resistant HL tumors in a human xenograft mouse model. In our phase 1 trial, the combination of BV and CsA was tolerable and produced an overall and complete response rate of 75% and 42% in a population of patients who were nearly all refractory to BV. Conclusions: This study may provide a new therapeutic strategy to combat BV resistance in HL. This is the first study reporting an effect of multidrug resistance modulation on the therapeutic activity of an antibody-drug conjugate in humans. The expansion phase of the trial is ongoing and enrolling patients who are refractory to BV to confirm clinical activity in this population with unmet need.