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Efficacy of Neoadjuvant Chemotherapy Combined with Anti-PD-1 Monoclonal Antibody in Locally Advanced Resectable Oral Squamous Cell Carcinoma: A Single-Arm Phase II Clinical Trial

ABSTRACT: Background: Neoadjuvant chemotherapy (NAC) combined with anti-PD-1 antibody is a potential treatment option for resectable oral squamous cell carcinoma (OSCC). It is important to be able to predict the effectiveness of NAC combined with anti-PD-1 antibody in clinical practice. Methods: In total, 30 patients with locally advanced, resectable OSCC (T3–T4, N0–N2, M0) who received two cycles of neoadjuvant chemoimmunotherapy (NACI) consisting of albumin-bound paclitaxel (250 mg/m2) and cisplatin (75 mg/m2) with the anti-PD-1 monoclonal antibody sintilimab (200 mg) were enrolled in this single-arm phase II trial. Twenty-three patients underwent surgical resection and seven received nonsurgical therapy. The primary and secondary end points were pathological response and clinical response, respectively. We utilized artificial intelligence (AI)-powered nuclear segmentation and classification to preliminarily assess the level of inflammatory cell infiltration in patients before NACI. Transcriptome RNA sequencing (RNA-seq) analysis was used to identify differentially expressed genes and immune cell subtypes between patients with and without major pathological response (MPR). Results: The MPR rate was 39.1% among 23 patients who underwent surgical resection. The objective response rate (ORR) was 43.3%. The primary location of OSCC was associated with the pathological response. There were no significant differences in the overall level of inflammatory cell infiltration between patients with and without MPR. Immune infiltration analysis of RNA-seq data revealed significant differences in the proportions of M1- and M2-type macrophages between the MPR and non-MPR groups. Conclusions: This study reveals the potential efficacy of NAC combined with anti-PD-1 antibody in treating OSCC patients, with acceptable side effects. This strategy can effectively inhibit clinical progression of locally advanced OSCC. The pathological response may be related to the degree of M1 macrophage infiltration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284162 | GEO | 2026/08/01

REPOSITORIES: GEO

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Project description:Background: Immunotherapy has been employed in the neoadjuvant treatment of locally advanced esophageal squamous cell carcinoma. To assess the feasibility of neoadjuvant radiotherapy combined with immunotherapy (NRIT), this study compares the efficacy and effectiveness of neoadjuvant chemoradiotherapy combined with immunotherapy (NICRT) and NRIT, while also exploring the underlying mechanisms of NRIT. Methods:This study retrospectively analyzed a cohort of 64 patients diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant therapy followed by esophagectomy between January 2019 and September 2023. Of these, 26 patients received neoadjuvant radiotherapy and immunotherapy (NRIT), while 38 patients were treated with neoadjuvant chemoradiotherapy (NICRT). The final analysis included pathological complete response (pCR), major pathological response (MPR), tumor regression grade (TRG), the rate of positive lymph node pCR, toxicity, surgical outcomes, postoperative complications, disease-free survival (DFS), and overall survival (OS). Additionally, paraffin-embedded tissue sections obtained before and after neoadjuvant NRIT were subjected to whole-exome sequencing, transcriptome sequencing, and immunohistochemistry (IHC) for programmed death-ligand 1 (PD-L1) analysis. Results: There was no significant difference in the rates of MPR and PCR (28.95% vs 30.77%, P=0.873), TRG classification (P=0.338), surgical outcomes, or postoperative complications (P=0.148), as well as overall survival (OS) and disease-free survival (DFS) between the NICRT and NRIT groups. However, a notable difference was observed in grade 3 or higher adverse events during treatment, with the NICRT group experiencing a higher incidence (34.21% vs 7.69%, P = 0.017) and severe hematological toxicity (23.68% vs 0.00%, P = 0.008). In the NRIT group, patients with high CPS scores demonstrated improved pathological responses. Pre-treatment genomic analyses indicated no differences in tumor mutation burden (TMB), somatic mutations, and copy number variations between MPR and non-MPR patients post-surgery. Transcriptome analysis revealed a significant number of differentially expressed genes in patients before and after treatment, closely associated with key pathways related to immunity. Following treatment, MPR patients exhibited a marked upregulation of the type I interferon response and the MHC class I antigen presentation pathway. Additionally, the number of B cells and monocytes increased, while non-MPR patients showed a significant downregulation of dendritic cells (DCs) after treatment, alongside the activation of various immune cells, including CD8 naïve cells, NK cells, and B cells. Conclusion: There was no significant difference between the NRIT group and the NICRT group regarding pathological response, surgical outcomes, postoperative complications, and survival analysis; furthermore, NRIT demonstrated a better safety profile compared to NICRT during treatment. Additionally, the mechanism of action of NRIT has been elucidated through a comprehensive analysis of genomic, transcriptomic, immunohistochemical, and other methods in conjunction with clinical results, thereby establishing NRIT as a neoadjuvant treatment that is both effective and safe.

Project description:Background and aims: Activation of the antitumor immune response using programmed death receptor-1 (PD-1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD-1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown. Approach and results: We recapitulated these clinical outcomes using orthotopic-grafted or induced-murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR-2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8-positive (CD8+ ) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor-associated macrophages and reducing T regulatory cell (Treg) and chemokine (C-C motif) receptor 2-positive monocyte infiltration in HCC tissue. In these models, VEGFR-2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD-ligand 1 expression in HCC cells was induced in a paracrine manner upon anti-VEGFR-2 blockade in endothelial cells in part through interferon-gamma expression. Moreover, we found that VEGFR-2 blockade increased PD-1 expression in tumor-infiltrating CD4+ cells. We also found that under anti-PD-1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti-VEGFR-2 antibody. Conclusions: We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti-PD-1 therapy-resistant and anti-PD-1 therapy-responsive HCC models.

Project description:Systemic chemotherapy, the standard first-line treatment option for patients with advanced oesophageal squamous cell carcinoma (OSCC), results in a median survival of approximately 1 year. Immune checkpoint inhibitors are a breakthrough oncology treatment option; however, most patients with advanced OSCC develop primary and acquired resistance to PD-1 monoclonal antibody, severely affecting their prognosis. Therefore, there is an urgent need to investigate the molecular mechanism underlying resistance to treatment. This study aimed to explore the mechanism of resistance to PD-1 monoclonal antibody. We collected plasma samples from patients with OSCC treated with immunotherapy, who achieved pathological response/partial response (CR/PR) or stable disease/progressive disease (SD/PD) after one treatment cycle. TM widely targeted metabolomics, widely targeted lipidomics, and DIA proteomics assays were performed. Differential metabolites were screened based on fold change (FC) ≥ 1.5 or ≤ 0.67 and a VIP ≥ 1; differential proteins were screened based on FC > 1.5 or < 0.67 and a p-value < 0.05. The identified metabolites were annotated and mapped using the KEGG pathway databases The differential proteins were annotated to the Gene Ontology and KEGG pathway databases. A correlation network diagram was drawn using differential expressed proteins and metabolites with (Pearson correlation coefficient) r > 0.80 and p-value <0.05. We finally screened 197 and 113 differential metabolites and proteins, respectively, in patients with CR/PR and SD/PD groups. The KEGG enrichment analysis revealed that all of these were enriched in cholesterol metabolism and in the NF-κB and phospholipase D signalling pathways. Our study is the first to demonstrate that PD-1 inhibitor resistance may be attributed to cholesterol metabolism or NF-κB and phospholipase D signalling pathway activation. This finding suggests that targeting these signalling pathways may be a promising novel therapeutic approach in OSCC which may improve prognosis in patients undergoing immunotherapy.

Project description:Introduction: MicroRNAs (miRNAs) are small non-coding RNA that play a vital role in cancer progression. Neo-adjuvant chemotherapy (NAC) has become the standard of care for locally advanced breast cancer. The aim of this study was to evaluate miRNA alterations during NAC using multiple samples of tissue and serum to correlate miRNA expression with clinico-pathological features and patient outcomes. Methods: Tissue and serum samples were collected from patients with locally advanced breast cancer undergoing NAC at four time points: time of diagnosis, after the first and fourth cycle of doxorubicin/cyclophosphamide treatment, and after the fourth cycle of docetaxel administration. First, we evaluated the miRNA expression profiles in tissue and correlated expression with clinico-pathological features. Then, a panel of four miRNAs (miR-451, miR-3200, miR-21, and miR-205) in serum samples was further validated using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). The alterations in serum levels of miRNA, associations with clinical and pathological responses, correlation with clinico-pathological features, and survival outcomes were studied using Friedman, Mann-Whitney U, Spearman, Wilcoxon signed-ranks tests. Pâ¤0.05 was considered statistically significant. Results: We analyzed 32 tissue samples and 108 serum samples from 8 patients and 27 patients, respectively. MicroRNA expression profiling of tumor versus normal tissue revealed more than 100 differentially expressed miRNAs. Serum miR-451 levels were significantly decreased during treatment, and higher serum levels were associated with improved clinical and pathological responses and disease-free survival. The serum levels of miR-3200 declined during NAC, and higher serum levels were associated with lower residual breast cancer burden and relapse rates. Conclusion: Variations in serum miRNA levels during NAC treatment may be therapeutically significant for predicting response and survival outcomes. Serum and tissue from a total of 27 consecutive patients diagnosed with locally advanced breast cancer undergoing NAC treatment were collected however microarray data were generated from tissue biopsy of 5 patients at four timepoints for both Normal and tumor. Additionally 3 tissue from only tumor at four timepoints and 6 patients at two timepoint T1 and T4

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Efficacy of Neoadjuvant Chemotherapy Combined with Anti-PD-1 Monoclonal Antibody in Locally Advanced Resectable Oral Squamous Cell Carcinoma: A Single-Arm Phase II Clinical Trial

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