Study On The Efficacy Of Neoadjuvant Chemotherapy Combined With Nivolumab In The Treatment Of Non-small Cell Lung Cancer

Objective: Non-small cell lung cancer is the most common subtype of lung cancer,accounting for 85% of lung cancer patients.Currently,the main treatments for non-small cell lung cancer include radiotherapy,chemotherapy,surgery,targeted,and immunotherapy.With the widespread use of immune checkpoint inhibitors,it has become one of the main modalities for the treatment of non-small cell lung cancer.But the safety and efficacy of the gradually emerging chemotherapy combined with immune checkpoint inhibitors for the treatment of non-small cell lung cancer are yet to be evaluated.Therefore,this study will evaluate the efficacy of chemotherapy combined with PD-1 inhibitor(nivolumab)in the treatment of patients with non-small cell lung cancer through a clinical trial and investigate the mechanism through animal studies.Methods: Clinical trial was conducted to explore the efficacy of the treatment modality.This clinical trial was a single-arm,Phase I clinical trial in which patients with stage I-IIIB non-small cell lung cancer were screened according to the enrollment criteria,and all patients enrolled were treated with carboplatin + paclitaxel + Nivolumab(PD-1 inhibitor).This trial used major pathologic response(MPR)as a surrogate endpoint.After surgery,tumor tissue was pathologically staged and patients were divided into MPR and non-MPR groups.Lung cancer tissues from 11 of these patients were selected for RNAseq,and differences in drug response between the two groups were explored by differential gene analysis,enriched pathway analysis,and CIBERSORT immune infiltration analysis.Subsequently,a murine-derived non-small cell lung cancer model was established by subcutaneous tumorigenesis of LLC cells。They were divided into 6 groups: control group(control),carboplatin group(carboplatin),paclitaxel group(paclitaxel),PD-1 inhibitor group(PD1),carboplatin + paclitaxel group(carboplatin+ paclitaxel),and carboplatin+paclitaxel+ PD-1 inhibitor group(carboplatin+ paclitaxel+ PD1).The differences in efficacy between different administration groups were compared,and finally immunohistochemical staining and real-time fluorescence quantitative PCR analysis were performed on mouse tumor tissues.Results: In the clinical setting,31 patients were collected from January 2021 to date,of which 70.96% were MPR patients.Compared to the reported clinical trials of NADIM,the MPR rate was 80%,so the current clinical trials have better efficacy.The results of RNAseq analysis showed that compared with MPR patients,non-MPR patients had more downregulated genes focused on major histocompatibility complex(MHC)presentation,toxic T cells,chemokine and interferon-γ(IFN-γ)activation pathways.Animal experiments showed the strongest tumor suppression in the carboplatin+paclitaxel+PD-1 inhibitor group among different dosing groups.In the results of real-time fluorescence quantitative PCR,compared with other administration groups,the carboplatin+paclitaxel+PD1 inhibitor group had the highest m RNA expression levels of immunologic cellular activity factor granzyme B(GZMB),IFN-γ and CC-like chemokine ligand5(CCL5),and the lowest expression of immunosuppressive transforming growth factor-β(TGF-β).Conclusion: Chemotherapy combined with PD-1 inhibitors had better efficacy in the treatment of non-small cell lung cancer,and immunerelated pathways were significantly suppressed in the non-MPR group.In animal experiments,the carboplatin + paclitaxel + PD-1 inhibitor group had the best tumor suppression effect compared with other groups of administration,and immune activation was more obvious in mouse tumor tissues.