gdc-0973 and Carcinoma

Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.

Topics: Animals; Antibodies, Monoclonal; Apoptosis; Azetidines; B7-H1 Antigen; Carcinoma; CD8-Positive T-Lymphocytes; Cell Cycle Checkpoints; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Drug Therapy; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Humans; Immunotherapy; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Neoplasm Transplantation; Piperidines