Efficacy Of PD-1 Inhibitors Research Articles

Blautia coccoides and its metabolic products enhance the efficacy of bladder cancer immunotherapy by promoting CD8+ T cell infiltration

BackgroundImmune checkpoint inhibitors (ICIs) have emerged as a novel and effective treatment strategy, yet their effectiveness is limited to a subset of patients. The gut microbiota, recognized as a promising anticancer adjuvant, is being increasingly suggested to augment the efficacy of ICIs. Despite this, the causal link between the gut microbiota and the success of immunotherapy is not well understood. This gap in knowledge has driven us to identify beneficial microbiota and explore the underlying molecular mechanisms.MethodsThrough 16S rDNA sequencing, we identified distinct gut microbiota in patients undergoing treatment with ICIs. Following this, we assessed the impact of probiotics on anti-PD-1 therapy in bladder cancer using mouse models, employing a multi-omics strategy. Subsequently, we uncovered the mechanisms through which Blautia-produced metabolites enhance antitumor immunity, utilizing untargeted metabolomics and a range of molecular biology techniques.ResultsIn our research, the LEfSe analysis revealed a significant enrichment of the Blautia genus in the gut microbiota of patients who responded to immunotherapy. We discovered that the external addition of Blautia coccoides hampers tumor growth in a bladder cancer mouse model by enhancing the infiltration of CD8+ T cells within the tumor microenvironment (TME). Further investigations through untargeted metabolomics and molecular biology experiments showed that oral administration of Blautia coccoides elevated trigonelline levels. This, in turn, suppresses the β-catenin expression both in vitro and in vivo, thereby augmenting the cancer-killing activity of CD8+ T cells.ConclusionsThis research provided valuable insights into enhancing the efficacy of PD-1 inhibitors in clinical settings. It was suggested that applying Blautia coccoides and its metabolic product, trigonelline, could serve as a synergistic treatment method with PD-1 inhibitors in clinical applications.Graphical

MA07.12 Unleashing the Potential of the Probiotic F.prausnitzii to Optimize PD-1 Inhibitor Efficacy in NSCLC Treatment

MA07.12 Unleashing the Potential of the Probiotic F.prausnitzii to Optimize PD-1 Inhibitor Efficacy in NSCLC Treatment

Efficacy of PD-1 inhibitor with neoadjuvant chemotherapy in hypopharyngeal and oropharyngeal cancer.

This study is aimed to evaluate the efficacy and safety of PD-1 inhibitors combined with neoadjuvant chemotherapy in patients with locally advanced hypopharyngeal and oropharyngeal cancer prior to surgical resection. This retrospective analysis included 42 patients diagnosed with locally advanced hypopharyngeal and oropharyngeal cancer. The efficacy, safety, survival, and laryngeal preservation rate were evaluated. A total of 42 patients were included in this retrospective analysis, of whom 28 had hypopharyngeal cancer and 14 had oropharyngeal cancer. Of the 42 patients, 14 (33.3%) achieved a pathological complete response (PCR) at the primary site, 20 (47.6%) achieved a major pathological response (MPR), and 8 (19%) had an incomplete pathological response (IPR) at the primary lesion. A PCR at both the primary site and the neck lymph nodes was observed in 9 patients (21.4%). The laryngeal preservation rate was 92.9% (26/28) in patients with hypopharyngeal cancer. The median follow-up time was 10.5 months. The median progression-free survival (PFS) was 26.42 months (95% CI, 23.416-29.424), and the median overall survival (OS) was 27.1 months (95% CI, 24.316-29.884). The 1-year PFS rate was 83.1%, and the 1-year OS rate was 85.9%. Combination therapy with PD-1 inhibitors and neoadjuvant chemotherapy has demonstrated superior efficacy and safety as a preoperative treatment for locally advanced hypopharyngeal and oropharyngeal cancer. Notably, this treatment regimen does not increase the risk of severe postoperative complications and has shown promising results in improving laryngeal preservation rates.

Irradiated tumor cell-released microparticles enhance the therapeutic efficacy of PD-1 inhibitors by promoting M1-TAMs polarization in NSCLC brain metastases

Brain metastases (BMs) are the most common sites of metastasis in patients with non-small cell lung cancer (NSCLC). However, BMs are not responsive to immunotherapy because of the blood-brain barrier. This is because intracranial immune cells such as M2 tumor-associated macrophages (TAMs) accumulate, creating an immunosuppressive tumor microenvironment. In this study, we focused on irradiated tumor cell-released microparticles (RT-MPs) that can cross the blood-brain barrier and influence the intracranial immune microenvironment. Using animal models of BMs, we observed that RT-MPs could penetrate the blood-brain barrier and be swallowed by TAMs. Then the microenvironment of TAMs is shifted from the M2 phenotype to the M1 phenotype, thereby modulating the interactions between TAMs and tumor cells. Single-cell sequencing analysis demonstrated that TAMs, after internalizing RT-MPs, active chemokine signaling pathways and secrete more chemokines, such as CCL5, CXCL2, CXCL1, CCL3, CCL4, and CCL22, attracting more CD4+ T cells and CD8+ T cells, improving immune-mediated killing, and enhancing subsequent combination anti-PD-1 therapy. These findings provide a preclinical foundation for exploring alternative treatments for patients with immunoresistant NSCLC BMs.

Tetrandrine activates STING/TBK1/IRF3 pathway to potentiate anti-PD-1 immunotherapy efficacy in non-small cell lung cancer

The efficacy of PD-1 therapy in non-small cell lung cancer (NSCLC) patients remains unsatisfactory. Activating the STING pathway is a promising strategy to improve PD-1 inhibitor efficacy. Here, we found tetrandrine (TET), an anti-tumor compound extracted from a medicinal plant commonly used in traditional Chinese medicine, has the ability to inhibit NSCLC tumor growth. Mechanistically, TET induces nuclear DNA damage and increases cytosolic dsDNA, thereby activating the STING/TBK1/IRF3 pathway, which in turn promotes the tumor infiltration of dendritic cells (DCs), macrophages, as well as CD8+ T cells in mice. In vivo imaging dynamically monitored the increased activity of the STING pathway after TET treatment and predicted the activation of the tumor immune microenvironment. We further revealed that the combination of TET with αPD-1 monoclonal antibody (αPD-1 mAb) yields significant anti-cancer effects by promoting CD8+ T cell infiltration and enhancing its cell-killing effect, which in turn reduced the growth of tumors and prolonged survival of NSCLC mice. Therefore, TET effectively eliminates NSCLC cells and enhances immunotherapy efficacy through the activation of the STING pathway, and combining TET with anti-PD-1 immunotherapy deserves further exploration for applications.

Efficacy of PD-1 inhibitors combined with nab-paclitaxel and cisplatin in the neoadjuvant treatment of locally advanced hypopharyngeal squamous cell carcinoma

Objective: To assess the efficacy of neoadjuvant treatment with PD-1 (programmed cell death protein 1) inhibitors combined with paclitaxel (albumin-conjugated) and cisplatin (TP regimen) for locally advanced hypopharyngeal squamous cell carcinoma and laryngeal organ function preservation. Methods: Data of 53 patients, including 51 males and 2 females, aged 38-70 years old, who were diagnosed with locally advanced hypopharyngeal squamous carcinoma confirmed by histology and enhanced CT at the Cancer Prevention and Control Center of Sun Yat-sen University during the initial treatment from January 1, 2019 to January 15, 2023, were retrospectively analyzed. All patients received neoadjuvant therapy with PD-1 inhibitors combined with albumin-bound paclitaxel (260 mg/m2) and cisplatin (60 mg/m2) for 3 to 4 cycles. The main outcome measures were larynx dysfunction-free survival (LDFS), overall survival (OS), and progression-free survival (PFS). Survival curves were plotted using the Kaplan-Meier method, and Cox multifactorial analysis was further performed if Cox univariate analysis was statistically significant. Results: The overall efficiency was 90.6% (48/53). The 1-year and 2-year LDFS rates were 83.8% (95%CI: 74.0% to 94.8%) and 50.3% (95%CI: 22.1% to 91.6%), the 1-year and 2-year OS rates were 95.2% (95%CI: 88.9% to 100.0%) and 58.2% (95%CI: 25.6% to 81.8%), and the 1-year and 2-year PFS rates were 83.9% (95%CI: 74.2% to 94.9%) and 53.5% (95%CI: 32.1% to 89.1%). Adverse events associated with the neoadjuvant therapy were mainly myelosuppression (45.3%), gastrointestinal reactions (37.7%) and hypothyroidism (20.8%). Conclusion: The neoadjuvant treatment of locally advanced hypopharyngeal squamous cell carcinoma using PD-1 inhibitors combined with paclitaxel and cisplatin can provide with a higher survival rate with a improved laryngeal organ function preservation rate.

Whole Exome Sequencing Reveals Gene Mutation Characteristics of Primary Central Nervous System Lymphoma

To investigate gene mutation characteristics of primary central nervous system lymphoma (PCNSL) through whole exome sequencing (WES) to 18 patients with PCNSL. Tumor tissues from 18 patients with diffuse large B-cell lymphoma who were diagnosed with PCNSL in Department of Hematology, Lanzhou University Second Hospital from September 2018 to December 2020 and had normal immune function, no history of HIV or immunosuppressant therapy were collected. High-throughput-based WES was performed on the tumor tissues, with an average sequencing depth of >100×. After data processing and bioinformatics analysis of sequencing results, the mutation maps and mutation characteristics of 18 PCNSL patients were obtained. Obvious somatic mutations were detected in all 18 patients. The median number of somatic mutations was 321. Missense mutations were most prominent (accounting for about 90%), and the mutation type was dominated by C>T (50.2%), reflecting the age-related mutation pattern. Among the top 15 frequently mutated genes, PSD3, DUSP5, MAGEB16, TELO2, FMO2, TRMT13, AOC1, PIGZ, SVEP1, IP6K3, and TIAM1 were the driver genes. The enrichment results of driver gene pathways showed that RTK-RAS, Wnt, NOTCH, Hippo and Cell-Cycle pathways were significantly enriched. The tumor mutation burden was between 3.558 48/Mb and 8.780 89/Mb, and the average was 4.953 32/Mb, which was significantly higher than other cancer research cohorts in the TCGA database. PCNSL occurs somatic missense mutations frequently, mainly point mutations, and the mutation type is mainly C>T. The driver genes are mainly involved in RTK-RAS, Wnt, NOTCH and Hippo pathways, indicating that the above pathways may be related to the pathogenesis of PCNSL. PCNSL has a significantly high tumor mutation burden, which may explain the efficacy of PD-1 inhibitors in PCNSL.

PD-1 inhibitor combined with paclitaxel and cisplatin in the treatment of recurrent and metastatic hypopharyngeal/laryngeal squamous cell carcinoma: efficacy and survival outcomes.

This retrospective study analyzed the efficacy of PD-1 inhibitors combined with albumin-bound paclitaxel and cisplatin (TP regimen) in the treatment of recurrent and metastatic hypopharyngeal/laryngeal squamous cell carcinoma (RMHSCC/RMLSCC). Patients diagnosed and treated at the Sun Yat-sen University Cancer Center from August 1, 2020, to August 15, 2023, with histologically confirmed RMHSCC/RMLSCC were included. All patients received PD-1 inhibitors combined with albumin-bound paclitaxel (260mg/m2) and cisplatin (60mg/m2) for 3-4 cycles. The primary endpoints were overall survival (OS) and progression-free survival (PFS). A total of 50 patients with RMHSCC/RMLSCC who received TP+PD-1 inhibitor therapy were included, with an objective response rate (ORR) of 56.0% (28/50). The 1-year and 2-year OS rates were 80.2% (95% CI: 69.3%-92.9%) and 68.6% (95% CI: 52.6%-89.5%), respectively, while the 1-year and 2-year PFS rates were 44.7% (95% CI: 31.9%-62.5%) and 26.0% (95% CI: 12.6%-53.4%), respectively. Treatment-related adverse events mainly included rash, myelosuppression, gastrointestinal reactions, and hypothyroidism. In the treatment of RMHSCC/RMLSCC with TP + PD-1 inhibitors, survival rates of patients can be improved while ensuring the safety of the treatment regimen.

Radiotherapy enhances efficacy of PD-1 inhibitors in advanced hepatocellular carcinoma: A propensity-matched real-world study.

To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma (HCC), combination with radiotherapy (RT) has emerged as a promising strategy. In preclinical studies, irradiated tumors released tumor antigens to synergistically increase the antitumor effect of immunotherapy. Hence, we investigated whether RT enhances the efficacy of anti-programmed death receptor-1 (PD-1) inhibitors in advanced HCC in real-world practice. Between August 2018 and June 2021, 172 patients with advanced primary HCC were enrolled in the tertiary center (Zhongshan Hospital of Fudan University); 95 were treated with a combination of RT and the inhibitor of PD-1 (RT-PD1 cohort), and 77 were administered anti-PD-1 therapy (PD1 cohort). The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with RT. Propensity score matching for bias reduction was used to evaluate the clinical outcomes. Among 71 propensity-matched pairs, median progression-free survival was 5.7 months in the RT-PD1 cohort vs. 2.9 months in the PD1 cohort ( P <0.001). Median overall survival was 20.9 months in the RT-PD1 cohort vs. 11.2 months in the PD1 cohort ( P =0.018). Compared with patients in the PD1 cohort, patients in the RT-PD1 cohort had significantly higher objective response rates (40.8%, 29/71 vs. 19.7%, 14/71, P =0.006) and disease control rates (62.0%, 44/71 vs. 31.0%, 22/71, P <0.001). The incidences of toxic effects were not significantly different between the two cohorts. RT plus anti-PD-1 therapy is well tolerated. RT enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.

A combined model of serum neutrophil extracellular traps, CD8+ Tcells, and tumor proportion score provides better prediction of PD-1 inhibitor efficacy in patients with NSCLC.

Immune checkpoint inhibitors provide a definite survival benefit for patients with driver-negative advanced non-small cell lung cancer (NSCLC), but predictors of efficacy are still lacking. There may be a relationship between immune inflammatory state and tumor immune response. We explored the relationship of serum neutrophil extracellular traps (NETs) with infiltrating cells in the tumor tissues of patients with NSCLC as well as their relationship with the therapeutic efficacy of programmed cell death protein 1 (PD-1) inhibitors. Serum myeloperoxidase (MPO)-double-stranded DNA (dsDNA) was detected as a marker of NET serum concentration. Tcells were detected by immunohistochemical staining, and neutrophils were counted by MPO immunofluorescence staining. Of the 31 patients with NSCLC, a longer progression-free survival after PD-1 inhibitor treatment was associated with higher levels of CD3+ Tcells, a lower neutrophil : CD3+-T-cell ratio (NEU/CD3+) and lower neutrophil : CD8+-T-cell ratio (NEU/CD8+) in tumor tissues. Patients with higher serum NETs were more likely to develop progressive disease after treatment (P = 0.003) and to have immune-related adverse events (IrAEs) as well as higher NEU/CD3+ and NEU/CD8+. The combined model of serum NETs, CD8+ Tcells, and tumor proportion score (TPS) significantly improved the prediction of PD-1 inhibitor efficacy [P = 0.033; area under the curve (AUC) = 0.881]. Our results indicate that serum NETs are effective predictors of PD-1 inhibitor response and reflect the tissue neutrophil-to-lymphocyte ratio and IrAE levels. The combined model of serum NETs, CD8+ Tcells, and TPS is a powerful tool for predicting the efficacy of PD-1 inhibitor treatment in patients with NSCLC.

Homologous-magnetic dual-targeted metal-organic framework to improve the Anti-hepatocellular carcinoma efficacy of PD-1 inhibitor

The insufficient abundance and weak activity of tumour-infiltrating lymphocytes (TILs) are two important reasons for the poor efficacy of PD-1 inhibitors in hepatocellular carcinoma (HCC) treatment. The combined administration of tanshinone IIA (TSA) and astragaloside IV (As) can up-regulate the abundance and activity of TILs by normalising tumour blood vessels and reducing the levels of immunosuppressive factors respectively. For enhancing the efficacy of PD-1 antibody, a magnetic metal–organic framework (MOF) with a homologous tumour cell membrane (Hm) coating (Hm@TSA/As-MOF) is established to co-deliver TSA&As into the HCC microenvironment. Hm@TSA/As-MOF is a spherical nanoparticle and has a high total drug-loading capacity of 16.13 wt%. The Hm coating and magnetic responsiveness of Hm@TSA/As-MOF provide a homologous-magnetic dual-targeting, which enable Hm@TSA/As-MOF to counteract the interference posed by ascites tumour cells and enhance the precision of targeting solid tumours. Hm coating also enable Hm@TSA/As-MOF to evade immune clearance by macrophages. The release of TSA&As from Hm@TSA/As-MOF can be accelerated by HCC microenvironment, thereby up-regulating the abundance and activity of TILs to synergistic PD-1 antibody against HCC. This study presents a nanoplatform to improve the efficacy of PD-1 inhibitors in HCC, providing a novel approach for anti-tumour immunotherapy in clinical practice.

Anlotinib may enhance the efficacy of anti-PD1 therapy by inhibiting the AKT pathway and promoting the apoptosis of CAFs in lung adenocarcinoma

Although PD-1 inhibitors have revolutionized the treatment paradigm of non-small cell lung cancer (NSCLC), their efficacy in treating NSCLC has remained unsatisfactory. Targeting cancer-associated fibroblasts (CAFs) is a potential approach for improving the immunotherapy response. Multitarget antiangiogenic tyrosine kinase receptor inhibitors (TKIs) can enhance the efficacy of PD-1 inhibitors in NSCLC patients. However, the effects and mechanisms of antiangiogenic TKIs on CAFs have not been elucidated. In this study, we first compared anlotinib with other antiangiogenic TKIs and confirmed the superior efficacy of anlotinib. Furthermore, we established NSCLC-associated CAF models and found that anlotinib impaired CAF viability and migration capacity and contributed to CAF apoptosis and cell cycle arrest in the G2/M phase. Moreover, anlotinib treatment attenuated the capacity of CAFs to recruit lung cancer cells and macrophages. Experiments in animal models suggested that anlotinib could enhance the efficacy of anti-PD1 therapy in NSCLC and affect CAF proliferation and apoptosis. Anlotinib increased the abundance of tumor-infiltrating CD8 + T cells, and PD-1 inhibitor-induced cytotoxicity to tumor cells was achieved through the transformation of the tumor microenvironment (TME) caused by anlotinib, which may partly explain the synergistic antitumor effect of anlotinib and PD-1 inhibitors. Mechanistically, anlotinib affects CAF apoptosis and cell viability at least in part by inhibiting the AKT pathway. In conclusion, our study suggested that anlotinib could regulate the TME, inhibit the AKT pathway and promote CAF apoptosis, providing new insights into the antitumor effect of anlotinib and improving the efficacy of immunotherapy.

Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer

BackgroundDynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays important roles in the activation, proliferation, and migration of T cells.MethodsWe investigated the synergistic effect of Drp1-mediated T cell antitumor activities and programmed cell death protein 1 (PD-1) blockade for treating lung cancer through in vitro co-culture experiments and an in vivo nude mouse xenograft model.ResultsHigh expression levels of Drp1 positively regulated T cell activation, enhanced T cell-induced suppression of lung cancer cells, promoted CD8+ T cell infiltration in the tumor and spleen, and significantly enhanced the antitumor immune response of the PD-1 inhibitor pembrolizumab. The mechanism of this synergistic antitumor effect involved the secretion of immune killing-related cytokines and the regulation of the PD-1-ERK/Drp1 pathway in T cells.ConclusionsOur findings suggest that modifying Drp1 expression in T cells could serve as a potential therapeutic target for enhancing the antitumor immune response in future immunotherapies.

Blockade of V-domain immunoglobulin suppressor of T-cell activation reprograms tumour-associated macrophages and improves efficacy of PD-1 inhibitor in gastric cancer.

In gastric cancer, the response rate of programmed cell death protein-1 (PD-1) inhibitor is far from satisfactory, indicating additional nonredundant pathways might hamper antitumour immunity. V-domain immunoglobulin suppressor of T-cell activation (VISTA) has been reported in several malignancies as a novel immune-checkpoint. Nevertheless, the role of VISTA in gastric cancer still remains obscure. Our purpose is to explore the clinical significance and potential mechanism of VISTA in affecting gastric cancer patients' survival and immunotherapeutic responsiveness. Our study recruited eight independent cohorts with a total of 1403 gastric cancer patients. Immunohistochemistry, multiplex immunofluorescence, flow cytometry or intracellular flow cytometry, quantitative polymerase chain reaction, western blotting, fluorescence-activated cell sorting, magnetic-activated cell sorting, smart-seq2, in vitro cell co-culture and ex vivo tumour inhibition assays were applied to investigate the clinical significance and potential mechanism of VISTA in gastric cancer. VISTA was predominantly expressed on tumour-associated macrophages (TAMs), and indicated poor clinical outcomes and inferior immunotherapeutic responsiveness. VISTA+ TAMs showed a mixed phenotype. Co-culture of TAMs and CD8+ T cells indicated that VISTA+ TAMs attenuated effective function of CD8+ T cells. Blockade of VISTA reprogrammed TAMs to a proinflammatory phenotype, reactivated CD8+ T cells and promoted apoptosis of tumour cells. Moreover, blockade of VISTA could also enhance the efficacy of PD-1 inhibitor, suggesting that blockade of VISTA might synergise with PD-1 inhibitor in gastric cancer. Our data revealed that VISTA was an immune-checkpoint associated with immunotherapeutic resistance. Blockade of VISTA reprogrammed TAMs, promoted T-cell-mediated antitumour immunity, and enhanced efficacy of PD-1 inhibitor, which might have implications in the treatment of gastric cancer.

Comprehensive molecular characteristics of clinical responses to PD-1 inhibitors plus anti-angiogenic agents (PA) in metastatic HER2-negative gastric adenocarcinoma.

279 Background: Anti-angiogensis agents were reported to enhance the efficacy of PD-1 inhibitor by inhibiting the infiltration of suppressive immune cell populations. Clinical studies indicated the synergistic anti-tumor effect of the combination of PD-1 inhibitors and anti-angiogenesis agents (PA). We aim to assess the efficacy of PA versus chemo-PA regiment in mGC, as well as the potential predictive biomarkers. Methods: A total of 55 GC tumors were analyzed using the next-generation sequencing (NGS), immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence (mIHC). Clinical outcomes [Disease Control Rate (DCR), Progression-free survival (PFS) and overall survival (OS)] were compared between patients receiving PA treatment (n=32) and chemo-PA (n=23) treatment. Exploratory biomarker analyses were conducted for the prediction for the efficacy of PA/chemo-PA treatment. Results: Patients receiving PA regiment had comparable DCR (69% vs 50%, P =0.25) and PFS (median PFS: 6.53 vs 4.73 months, HR=0.70, 95%CI: 0.27-1.78, P =0.52), compared with those treated with combination of chemo-PA regiment as second or later-line treatment in mGC. Patients with HMCN1 wild-type showed significant improvements in DCR (77% vs 0%, P =0.023) and PFS (median PFS: 6.53 vs 1.17 months, P =0.0017), versus those with HMCN1 mutations in PA treatment cohort. HMCN1 mutations are associated with lower infiltration of endothelial cells and lower score of VEGF ligand-receptor interaction, according to the EPIC and pathway enrichment analysis ( P &lt; 0.05). In addition, analysis of TIME by mIHC revealed that the fraction of CD68+ tumor-associated macrophages in the tumor center was higher in responders than non-responders before treatment (median: 17.59% vs 2.45%, P=0.016). Conclusions: PA regiment and chemo-PA regiment had similar efficacy in second or later line treatment of mGC. HMCN1 mutations maybe a predictive marker for PA regiment in HER2-negative mGC, which should be further validated in a large cohort.

The impact of sarcopenia on the efficacy of PD-1 inhibitors in non-small cell lung cancer and potential strategies to overcome resistance.

Recent studies have revealed that sarcopenia can adversely affect the efficacy of PD-1 inhibitors in the treatment of non-small cell lung cancer (NSCLC). PD-1 inhibitors are immune checkpoint inhibitors widely used in the treatment of various cancers. However, NSCLC patients may have poorer outcomes when receiving PD-1 inhibitor treatment, and sarcopenia may affect the efficacy of PD-1 inhibitors through immune and metabolic mechanisms. In this article, we summarize the reported negative impact of sarcopenia on the effectiveness of PD-1 inhibitors in the treatment of NSCLC in recent years. Based on existing research results, we analyze the possible mechanisms by which sarcopenia affects the efficacy of PD-1 inhibitors and discuss possible strategies to address this issue. This could help to understand the impact of sarcopenia on the treatment of PD-1 inhibitors and provide more accurate expectations of treatment outcomes for clinicians and patients. Additionally, we present tailored intervention strategies for sarcopenic patients undergoing PD-1 inhibitor therapy, aiming to optimize treatment efficacy and enhance patient quality of life. Nevertheless, further research is warranted to elucidate the mechanisms through which sarcopenia impacts PD-1 inhibitors and to identify more efficacious intervention approaches for improving the effectiveness of PD-1 inhibitor treatment in sarcopenic patients.

Shenling Baizhu Decoction (SLBZD) may play a synergistic role of tirelizumab in the treatment of colorectal cancer by influencing the imbalance of colon flora and Tumor microenvironment.

Objective: To explore whether SLBZD can play a synergistic role in promoting the efficacy of PD-1 inhibitors in the treatment of colorectal cancer by influencing the intestinal microenvironment and Tumor microenvironment. Method: Shenling Baizhu Decoction (SLBZD) and tirelizumab (TLzmab) treated the colorectal mouse model. The tumor growth rate, tumor weight, and tumor growth inhibition rate were evaluated. Fecal microbiota was detected by 16S rDNA sequencing and immune cell was detected by the flow cytometry analysis. Result: Compared to tumor weight, there exist significant differences between each group among the three groups. Compared to tumor volume, there was no statistically significant difference in tumor size between the control group and the TLzmab group at 7 days. However, there was a statistical difference in tumor size among the three groups at 18 days. By analyzing the diversity of the Gut microbiota, the diversity decreased after TLzmab treatment with a statistically significant difference. Compared with the control group, the diversity of the TLzmab+SLBZD group increased. The proportion of lymphocytes in the blood was analyzed by flow cytometry. Compared with the control group, Myeloid-derived suppressor cells (MDSCs) decreased and T regulatory cells (Treg) increased significantly in the TLzmab group. Compared with the control group and TLzmab group, the TLzmab+SLBZD group showed a significant increase in M1 type macrophages, while the M2 type macrophages, MDSCs, and Treg showed a significant decrease. Conclusion: An imbalance of Gut microbiota and imbalance of tumor immune microenvironment will occur during TLzmab treatment, which will lead to poor therapeutic effect of TLzmab or drug resistance. SLBZD will increase the abundance of Gut microbiota, which will lead to the increase of M1 macrophages in the tumor immune microenvironment and the decrease of M2 macrophages and Treg cells, thus exerting the synergistic effect of TLzmab. This study provides a new way to explore the improvement of ICIs through traditional Chinese medicine.

Effect of AGEs-RAGE system on the efficacy of PD-1 inhibitors in the treatment of driver-gene mutation negative advanced non-squamous non-small cell lung cancer.

To observe the therapeutic effect of PD-1 inhibitors on driver-gene mutation negative advanced non-squamous non-small cell lung cancer (nsNSCLC) and the role of the AGEs-RAGE system in the disease, provide more reliable treatment for future nsNSCLC patients. In this study, we selected 130 nsNSCLC patients admitted between January 2021 and April 2022 were selected as the study subjects, 61 of whom received pemetrexed plus carboplatin (control group) and 69 received PD-1 inhibitors, pemetrexed and carboplatin (research group). The clinical efficacy and adverse reactions of the two groups were compared, and the prognostic survival time was calculated. The results show that two groups were not statistically different in objective response rate (ORR) and incidence of adverse reactions, but the disease control rate (DCR) was higher in the research group (P<0.05). Besides, the median progression-free survival (PFS) was prolonged in the research group compared with the control group (P<0.05). In addition, changes in the levels of T lymphocyte subsets, AGEs and RAGE before and after treatment were detected, and the relationship between AGEs-RAGE and the therapeutic effect of PD-1 inhibitors was analyzed. The research group also showed higher CD3+, CD4+ and lower CD8+, AGEs and RAGE levels than the control group after treatment (P<0.05). Finally, we found that in addition, the efficacy of the study group was inversely related to AGEs and RAGE levels (P<0.05). With these results, we concluded that PD-1 inhibitors are effective in the treatment of driver-gene mutation negative advanced nsNSCLC, and the AGEs-RAGE system may provide a more reliable guarantee for the treatment outcomes of patients in the future.

Clinicopathological characteristics and treatment outcomes of advanced SMARCA4-deficient thoracic tumors.

SMARCA4-deficient thoracic tumors, characterized by distinct clinicopathological, morphological, immunohistochemical, and genetic features, differ significantly from conventional non-small-cell lung carcinomas (NSCLCs). This group encompasses both SMARCA4-deficient NSCLCs (SMARCA4-NSCLCs) and SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs). The efficacy of PD-1 inhibitors in treating SMARCA4-deficient thoracic tumors remains uncertain. Medical records of 36 patients diagnosed with stage IIIB, IIIC, or IV SMARCA4-deficient thoracic tumors were analyzed. We assessed the clinical, pathological, and genetic features of these patients through immunohistochemistry (IHC) and a 68-gene panel next-generation sequencing (NGS). We compared the differences between SMARCA4-NSCLCs and SMARCA4-UTs, and evaluated the impact of chemotherapy and immunotherapy on patient outcomes. The majority of patients with SMARCA4-deficient thoracic tumors were heavy-smoking males, averaging 64.6 years in age. IHC predominantly showed weak or negative staining for markers such as TTF-1, CK5/6, p40, synaptophysin, chromogranin A, and CD56, which are often associated with adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumors. The most common genetic mutations identified via NGS included TP53, CDKN2A, KRAS, STK11, NF1, and PTEN. No significant overall survival (OS) difference was observed between SMARCA4-NSCLCs and SMARCA4-UTs (p = 0.366). The median OS for patients treated with chemotherapy (n = 9) was 447 days, while the median OS for patients undergoing PD-1-inhibitor-based therapy (n = 16) was not reached (p = 0.105). SMARCA4-deficient thoracic tumors exhibit distinct characteristics from conventional NSCLCs, and PD-1 inhibitors show promise in treating advanced SMARCA4-deficient thoracic tumors.

PD-1 inhibitors combined with paclitaxel and cisplatin in first-line treatment of esophageal squamous cell carcinoma (ESCC): a network meta-analysis

BackgroundThe combinations of PD-1 inhibitors with paclitaxel/cisplatinum (PD-1 + TP) and fluoropyrimidine/cisplatinum (PD-1 + FP) both have been shown to improve overall survival (OS) and progression-free survival (PFS) in patients with previously untreated, advanced esophageal squamous cell carcinoma (ESCC). However, there is no consensus on which chemotherapy regimen combined with PD-1 has better efficacy. To deal with this important issue in the first-line treatment of patients with ESCC, a network meta-analysis (NMA) was performed.MethodsData were collected from eligible studies searched in Medline, Web of Science, PubMed, the Cochrane Library and Embase. The pooled hazard ratio (HR) for the OS, and PFS, odds ratio (OR) for the objective response rate (ORR) and ≥ 3 grade treatment-related adverse events (≥ 3TRAEs) were estimated to evaluate the efficacy of PD-1 inhibitors combined with TP or FP.ResultsFive RCTs and one retrospective study involving 3685 patients and evaluating four treatments were included in this NMA. Compared to other treatments, PD-1 + TP was better. For the PFS, the HRs for PD-1 + TP compared to PD-1 + FP, TP and FP were 0.59 (0.44, 0.80), 0.56 (0.51, 0.61) and 0.45 (0.37, 0.56) respectively. For the OS, PD-1 + TP was also a better treatment compared to other treatments. The HRs were 0.74 (0.56, 0.96), 0.64 (0.57, 0.71), 0.53 (0.43, 0.67) respectively. For the ORR, there was no significant difference between PD-1 + TP and PD-1 + FP, and the ORs were 1.2 (0.69, 2.11). Compare with TP and FP, PD-1 + TP had an obvious advantage, ORs were 2.5 (2.04, 3.04) and 2.95 (1.91, 4.63). For ≥ 3TRAEs, PD-1 + TP compared to other treatments, ORs were 1.34 (0.74, 2.46) and 1.13 (0.92, 1.38) and 2.23 (1.35, 3.69).ConclusionPD-1 + TP significantly improved both PFS and OS compared to PD-1 + FP. Taking into account both efficacy and safety, PD-1 + TP may be a superior first-line treatment option for ESCC.