Assuntos
Ambulâncias/estatística & dados numéricos , Segurança do Paciente/estatística & dados numéricos , Medicina Estatal/organização & administração , Carga de Trabalho/psicologia , Ambulâncias/provisão & distribuição , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/virologia , Inglaterra/epidemiologia , Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Necessidades e Demandas de Serviços de Saúde/tendências , Humanos , Liderança , Admissão do Paciente/estatística & dados numéricos , Admissão do Paciente/tendências , Segurança do Paciente/normas , SARS-CoV-2/genética , Estações do Ano , Carga de Trabalho/estatística & dados numéricosRESUMO
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.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Linfócitos T CD8-Positivos/imunologia , Imunoconjugados/farmacologia , Morte Celular Imunogênica , Linfoma/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Apoptose , Antígeno de Maturação de Linfócitos B/imunologia , Proliferação de Células , Feminino , Humanos , Linfoma/imunologia , Linfoma/metabolismo , Linfoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo. EXPERIMENTAL DESIGN: Immune effects of dabrafenib and trametinib were evaluated in human CD4(+) and CD8(+) T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model. RESULTS: Dabrafenib enhanced pERK expression levels and did not suppress human CD4(+) or CD8(+) T-cell function. Trametinib reduced pERK levels, and resulted in partial/transient inhibition of T-cell proliferation/expression of a cytokine and immunomodulatory gene subset, which is context dependent. Trametinib effects were partially offset by adding dabrafenib. Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild-type tumor cells induced apoptosis markers, upregulated HLA molecule expression, and downregulated certain immunosuppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA. PD-L1 expression in tumor cells was upregulated after acquiring resistance to BRAF inhibition in vitro. Combinations of trametinib with immunomodulators targeting PD-1, PD-L1, or CTLA-4 in a CT26 model were more efficacious than any single agent. The combination of trametinib with anti-PD-1 increased tumor-infiltrating CD8(+) T cells in CT26 tumors. Concurrent or phased sequential treatment, defined as trametinib lead-in followed by trametinib plus anti-PD-1 antibody, demonstrated superior efficacy compared with anti-PD-1 antibody followed by anti-PD-1 plus trametinib. CONCLUSION: These findings support the potential for synergy between targeted therapies dabrafenib and trametinib and immunomodulatory antibodies. Clinical exploration of such combination regimens is under way.