Background RAS is one of the most frequently mutated oncogenes in lung cancer. The KRAS G12C mutation is present in approximately 39% of KRAS-mutant NSCLC.1 Mutant KRAS is linked to PD-L1 expression, and oncogenic RAS signaling promotes an immunosuppressive tumor microenvironment by upregulating PD-L1 expression. Consequently, combining KRAS G12C inhibitors with immune checkpoint blockers shows promising benefits. Highly immunodeficient mice are transplanted with human PBMC or CD34+ cells, providing an opportunity to evaluate candidates targeting human immune system in pre-clinical tumor models. In this study, we evaluated the combination efficacy of KRAS G12C inhibitor AMG510 and anti-PD-1 antibody Nivolumab in humanized NSCLC mouse models, revealing strong rationale for clinical practice.
Methods LU-01–0361 was a patient-derived xenograft model of NSCLC that exhibited both KRAS G12C mutation and high PD-L1 expression. To better understand the mechanisms underlying the combined inhibition of AMG510 and Nivolumab, LU-01–0361 tumor model was established in human PBMC and CD34+ cells transplanted humanized mice respectively. Tumor growth and body weight were monitored, blood and tumor samples were collected. Immune profiling analysis of human immune cell reconstitution and infiltration were conducted by flow cytometry, spatial transcriptomics and CITE-seq.
Results In both PBMC-LU-01–0361 and CD34+-LU-01–0361 models, adding Nivolumab to AMG510 delayed tumor growth compared with AMG510 alone. In PBMC-LU-01–0361 model, tumor regression (TR=82%) occurred in all mice after AMG510 plus Nivolumab treatment (figure 1 A, B, C). Similarly, in vivo tumor growth inhibition (TGI= 56%) was observed after combination treatment compared with AMG510 alone in the CD34+-LU-01–0361 model (figure 1 D, E, F). Furthermore, the administration of AMG510 sensitized the tumor microenvironment by upregulating antigen presentation and immune activation related genes, enhancing MHC-related antigen presentation signal pathways and immune cell activation signal pathways. The combination treatment of AMG510 and Nivolumab greatly improved the benefits of immunotherapy.
Conclusions KRAS G12C mutation and PD-L1 overexpression in cancer patients contribute to immune suppression. Combination therapy of KRAS G12C inhibitor AMG510 and anti-PD-1 antibody Nivolumab demonstrated significant anti-tumor activities in pre-clinical humanized NSCLC mouse models. Notably, AMG510 provided complementary immune modulatory benefits that support the mechanism of Nivolumab. The findings suggest that combining KRAS G12C inhibitor with anti-PD-1 antibody holds a promising therapeutic potential for NSCLC patients.
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