비소세포폐암에서 항 PD-1 항체와 병용하는 자가 NK세포 요법

Abstract

Background: Although the new development of immune checkpoint inhibitors (ICIs) has led to advances in non-small cell lung cancer (NSCLC) treatment, the low response rates to ICIs are still a problem. Since natural killer (NK) cells participate in the immune response against cancer cells, the development of NK cell-mediated immunotherapies has the potential to be a strategy to increase the efficacy of current T cell-mediated immunotherapies. This study was conducted to evaluate the role of NK cells in anti-PD-1 therapy and assess the efficacy of autologous NK cell therapy in combination with anti-PD-1 antibody (Ab) in NSCLC. Materials and Methods: Non-genetically modified, ex-vivo culture expanded human NK cells (SNK01) were generated through an NK cell activation process. The role of NK cells in the antitumor immune response elicited by anti-PD-1 therapies and the in vivo efficacy of SNK01 and anti-PD-1 Ab combination therapy compared to anti-PD-1 monotherapy were evaluated in a mouse model. Based on these preclinical results, we analyzed immune cell counts and cytokine levels according to treatment response, timepoint (pre- vs. post-NK cell therapy) and treatment group to evaluate the mechanisms underlying anti-PD-1 Ab and SNK01 combination therapy. Results: In a mouse model with PD-L1-overexpressing mouse NSCLC cells, when mice were depleted of NK or T cells, anti-PD-1 Ab treatment was ineffective, while the treatment was effective in undepleted mice. This result suggests that PD-1 blockade mobilizes an NK cell and T cell response, and NK cells contribute to the therapeutic effect of PD-1 blockade. SNK01 and anti-PD-1 Ab combination therapy resulted in enhanced growth inhibition of xenograft tumors of human NSCLC cells in NOD-rag1-/-Il2rgnull (NRG) mouse models, regardless of PD-L1 expression status, suggesting that combination therapy would be also effective in PD-L1–negative NSCLC. In the clinical study with NSCLC patients, treatment responders (n=5) showed a tendency towards higher baseline NK activity than non-responders (n=13; p=0.01). Otherwise, there were no significant differences in immune cell counts and cytokine levels according to treatment group, treatment response or timepoint (pre- vs. post-treatment). Conclusion: Based on the findings of this study, the NK cell therapy combined with anti-PD-1 Ab may be considered as a treatment option for NSCLC.