TY - JOUR
T1 - Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses in Vivo
AU - de Oca, Rocio Montes
AU - Alavi, Alireza S.
AU - Vitali, Nick
AU - Bhattacharya, Sabyasachi
AU - Blackwell, Christina
AU - Patel, Krupa
AU - Seestaller-Wehr, Laura
AU - Kaczynski, Heather
AU - Shi, Hong
AU - Dobrzynski, Eric
AU - Obert, Leslie
AU - Tsvetkov, Lyuben
AU - Cooper, David C.
AU - Jackson, Heather
AU - Bojczuk, Paul
AU - Forveille, Sabrina
AU - Kepp, Oliver
AU - Sauvat, Allan
AU - Kroemer, Guido
AU - Creighton-Gutteridge, Mark
AU - Yang, Jingsong
AU - Hopson, Chris
AU - Yanamandra, Niranjan
AU - Shelton, Christopher
AU - Mayes, Patrick
AU - Opalinska, Joanna
AU - Barnette, Mary
AU - Srinivasan, Roopa
AU - Smothers, James
AU - Hoos, Axel
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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 CD8þ 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.
AB - 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 CD8þ 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.
UR - http://www.scopus.com/inward/record.url?scp=85117713409&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-21-0035
DO - 10.1158/1535-7163.MCT-21-0035
M3 - Article
C2 - 34253590
AN - SCOPUS:85117713409
SN - 1535-7163
VL - 20
SP - 1941
EP - 1955
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 10
ER -