Brentuximab vedotin for CD30-positive tumours

Abstract

According to a recent Review in The Lancet Oncology, only two antibody–drug conjugates have been approved by the US Food and Drug Administration (FDA)—brentuximab vedotin and ado-trastuzumab emtansine. Brentuximab vedotin was approved in 2011 and targets CD30-positive cells for the treatment of refractory Hodgkin’s lymphoma and anaplastic large-cell lymphoma. Recently, 5-year follow-up results were reported for patients with refractory Hodgkin’s lymphoma showing that brentuximab vedotin had good disease control (41% overall survival and 22% progression-free survival; NCT00848926). Because CD30 expression on normal cells is restricted, “on-target, off-tumour” toxicity is kept to a minimum. But why does brentuximab vedotin achieve such astonishing results? Although paradoxical, both “on-target eff ects” and local “off-target effects” could explain this occurrence. Three important studies have been published recently that might help explain why this is. First, the Seattle Genetics group report on bystander killing (the killing of neighbouring cells irrespective of their antigen expression by antibodydrug conjugates). By establishing preclinical models that harbour tumour heterogeneity, investigators found that membrane permeable monomethyl auristatin E (cytotoxic payload) is potent in diff using from CD30-positive target cells, and that close bystander cells might receive cytotoxic monomethyl auristatin E non-specifically. Second, another study proposes that CD30-positive tumour cells release CD30-expressing extracellular vesicles that bind to CD30 ligands on bystander cells, thereby making them the target of brentuximab vedotin. Since this is an in vitro model, however, further examination of clinical samples would be needed to explore whether CD30-expressing extracellular vesicles are released in patient samples, and whether CD30-ligand cells are existing and functional in patients. In another study, epigenetic-induced expression of CD30 enabled successful treatment with brentuximab vedotin (of eight patients with T-cell prolymphocytic leukaemia, seven patients had a complete response and one had a partial response), although the treated patients had T-cell prolymphocytic leukaemia. Epigenetic therapy with drugs such as cladribine and vorinostat, was able to induce CD30 expression in tumours, and subsequent treatment with brentuximab vedotin overcame treatment resistance, suggesting that the combination of epigenetic therapy and antibody–drug conjugate administration would be a novel strategy for treatment-resistant tumours. This report is outstanding because clinical responses were actually observed in several patients with T-cell prolymphocytic leukaemia. Taken together, these studies show that brentuximab vedotin is proving to be a promising drug although its mechanism of action should be further clarifi ed. Other antibody–drug conjugates currently in development should be fully validated in the same way to see if they have the same therapeutic potential.