Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses<i>In Vivo</i>
Rocío Montes de, Alireza Alavi, Nick Vitali, Sabyasachi Bhattacharya, Christina Blackwell, Krupa Patel, Laura Seestaller‐Wehr, Heather Kaczynski, Hong Shi, Eric Dobrzynski, Leslie Obert, Lyuben Tsvetkov, David C. Cooper, Heather L. Jackson, Paul Bojczuk, Sabrina Forveille, Oliver Kepp, Allan Sauvat, Guido Kroemer, Mark Creighton-Gutteridge, Jingsong Yang, Chris Hopson, Niranjan Yanamandra, Christopher A. Shelton, Patrick A. Mayes, Joanna Opalinska, Mary S. Barnette, Roopa Srinivasan, James Smothers, Axel Hoos
Abstract
Abstract B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody–drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to rechallenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8+ T cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance antitumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell–directed checkpoint modulators.