Efficacy In Non-small Cell Lung Cancer Research Articles

FGL1: a novel biomarker and target for non-small cell lung cancer, promoting tumor progression and metastasis through KDM4A/STAT3 transcription mechanism

Non-small cell lung cancer (NSCLC) is characterized by a high incidence rate and poor prognosis worldwide. A deeper insight into the pathogenesis of NSCLC and identification of novel therapeutic targets are essential to improve the prognosis of NSCLC. In this study, we revealed that fibrinogen-like protein 1 (FGL1) promotes proliferation, migration, and invasion of NSCLC cells. Mechanistically, we found that Stat3 acts as a transcription factor and can be recruited to the FGL1 promoter, enhancing FGL1 promoter activity. Lysine-specific demethylase 4A (KDM4A) interacts with Stat3 and facilitates the removal of methyl groups from H3K9me3, thereby enhancing Stat3-mediated transcription of FGL1. Furthermore, we observed that Stat3 and KDM4A promote NSCLC cell proliferation, migration, and invasion partly by upregulating FGL1 expression. Additionally, the expression of FGL1 was significantly higher in cancer tissues (n = 90) than in adjacent non-cancerous tissues (n = 90). Furthermore, patients with high FGL1 expression had a shorter overall survival (OS) compared to those with low FGL1 expression. We measured the expression levels of FGL1 on circulating tumor cells (CTCs) in 65 patients and found that patients with a dynamic decrease in FGL1 expression on CTCs exhibited a better therapeutic response. These findings suggest that the dynamic changes in FGL1 expression can serve as a potential biomarker for predicting treatment efficacy in NSCLC. Overall, this study revealed the significant role and regulatory mechanisms of FGL1 in the development of NSCLC, suggesting its potential as a therapeutic target for patients with NSCLC. Future studies should provide more personalized and effective treatment options for patients with NSCLC to improve clinical outcomes.

Research Progress on Predictive Biomarkers of Immunotherapy Efficacy in Non-small Cell Lung Cancer

Lung cancer is one of the most common malignant tumors in the world, of which non-small cell lung cancer (NSCLC) is the majority. The emergence of immune checkpoint inhibitors (ICIs) has greatly changed the treatment strategy of NSCLC and improved the prognosis of patients. However, in reality, only a small number of patients can achieve long-term benefit. Therefore, the identification of reliable predictive biomarkers is essential for the selection of treatment modalities. With the development of molecular biology and genome sequencing technology in recent years, as well as the in-depth understanding of tumor and its host immune microenvironment, research on biomarkers has emerged in an endless stream. This review focuses on the predictive biomarkers of immunotherapy efficacy in NSCLC, in order to provide some guidance for precision immunotherapy. .

NAT10-mediated upregulation of GAS5 facilitates immune cell infiltration in non-small cell lung cancer via the MYBBP1A-p53/IRF1/type I interferon signaling axis

Interactions of tumor cells with immune cells in the tumor microenvironment play an important role during malignancy progression. We previously identified that GAS5 inhibited tumor development by suppressing proliferation of tumor cells in non-small cell lung cancer (NSCLC). Herein, we discovered a tumor-suppressing role for tumor cell-derived GAS5 in regulating tumor microenvironment. GAS5 positively coordinated with the infiltration of macrophages and T cells in NSCLC clinically, and overexpression of GAS5 promoted macrophages and T cells recruitment both in vitro and in vivo. Mechanistically, GAS5 stabilized p53 by directly binding to MYBBP1A and facilitating MYBBP1A-p53 interaction, and enhanced p53-mediated transcription of IRF1, which activated type I interferon signaling and increased the production of downstream CXCL10 and CCL5. We also found that activation of type I interferon signaling was associated with better immunotherapy efficacy in NSCLC. Furthermore, the stability of GAS5 was regulated by NAT10, the key enzyme responsible for N4-acetylcytidine (ac4C) modification, which bound to GAS5 and mediated its ac4C modification. Collectively, tumor cell-derived GAS5 could activate type I interferon signaling via the MYBBP1A-p53/IRF1 axis, promoting immune cell infiltration and potentially correlating with immunotherapy efficacy, which suppressed NSCLC progression. Our results suggested GAS5 as a promising predictive marker and potential therapeutic target for combination therapy in NSCLC.A schematic diagram demonstrating the regulatory effect of GAS5 on immune cell infiltration by activating type I interferon signaling via MYBBP1A-p53/IRF1 axis in non-small cell lung cancer. IFN, interferon.

Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production

Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such as Auranofin, are effective in eradicating cancer cells. However, the clinical significance of thioredoxin reductase 1 (TrxR1) in lung cancer, as well as the potential for its antagonist as a treatment option, necessitated further experimental validation. In this study, we observed significant upregulation of TrxR1 specifically in non-small cell lung cancer (NSCLC), rather than small cell lung cancer. Moreover, TrxR1 expression exhibited associations with survival rate, tumor volume, and histological classification. We developed a novel TrxR1 inhibitor named LW-216 and assessed its antitumor efficacy in NSCLC. Our results revealed that LW-216 is effectively bound with intracellular TrxR1 at sites R371 and G442, facilitating TrxR1 ubiquitination and suppressing TrxR1 expression, while not affecting TrxR2 expression. Treatment of LW-216-induced DNA damage and cell apoptosis in NSCLC cells through the generation of reactive oxygen species (ROS). Importantly, supplementation with N-acetylcysteine (NAC) or ectopic TrxR1 expression reversed LW-216-induced apoptosis. Furthermore, LW-216 displayed potent tumor growth inhibition in NSCLC cell-implanted mice, reducing TrxR1 expression in xenografts. Remarkably, LW-216 exhibited superior antitumor activity compared to Auranofin in vivo. Collectively, our research provides compelling evidence supporting the potential of targeting TrxR1 by LW-216 as a promising therapeutic strategy for NSCLC.

Efficacy of Sorafenib-Based Therapies for Non-Small Cell Lung Cancer.

Lung cancer remains the leading cause of cancer-related deaths, with a poor prognosis. Of the two types, non-small cell lung cancer (NSCLC) is the major and most prevalent type and associated with low response rates to the current treatment options. Sorafenib, a multitargeted tyrosine kinase inhibitor used for various malignancies, gained attention for its potential efficacy in NSCLC. This review paper focuses on the findings of recent in vitro, in vivo, and clinical studies regarding the efficacy of sorafenib. Overall, sorafenib has shown definitive therapeutic potential in NSCLC cell lines, xenografts, and human subjects. Novel approaches to sorafenib delivery may improve its efficacy and should be the focus of further studies.

Babaodan overcomes cisplatin resistance in cholangiocarcinoma via inhibiting YAP1

Context Cholangiocarcinoma with highly heterogeneous, aggressive, and multidrug resistance has a poor prognosis. Although babaodan (BBD) combined with cisplatin improved non-small cell lung cancer efficacy, its impact on overcoming resistance in cholangiocarcinoma remains unexplored. Objective This study explored the role and mechanism of BBD on cisplatin resistance in cholangiocarcinoma cells (CCAs). Materials and methods Cisplatin-resistant CCAs were exposed to varying concentrations of cisplatin (25–400 μg/mL) or BBD (0.25–1.00 mg/mL) for 48 h. IC50 values, inhibition ratios, apoptosis levels, DNA damage, glutathione (GSH) levels, oxidized forms of GSH, total GSH content, and glutaminase relative activity were evaluated using the cell counting kit 8, flow cytometry, comet assay, and relevant assay kits. Results BBD-reduced the cisplatin IC50 in CCAs from 118.8 to 61.83 μg/mL, leading to increased inhibition rate, apoptosis, and DNA damage, and decreased expression of B-cell lymphoma-2, p-Yes-associated protein 1/Yes-associated protein 1, solute carrier family 1 member 5, activating transcription factor 4, and ERCC excision repair 1 in a dose-dependent manner with maximum reductions of 78.97%, 51.98%, 54.03%, 56.59%, and 63.22%, respectively; bcl2-associated X and gamma histone levels were increased by 0.43–115.77% and 22.15–53.39%. The impact of YAP1 knockdown on cisplatin-resistant CCAs resembled BBD. GSH, oxidized GSH species, total GSH content, and glutaminase activity in cisplatin-resistant CCAs with BBD treatment also decreased, while YAP1 overexpression countered BBD’s effects. Discussion and conclusion This study provides a scientific basis for BBD clinical application and provides a new direction for BBD biological mechanism research.

CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient Tcell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced Tcell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ Tcells, as well as CXCR3-dependent Tcell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.

A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor.

AMG510, as the first approved inhibitor for KRASG12C mutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRASG12C mutation. However, the moderate response rate and the rapid emergence of acquired resistance limit the therapeutic potential of AMG510, highlighting the need for the development of combination strategies. Here, we observed the suppression of RAS-MAPK signaling induced by AMG510 was prolonged and enhanced by SOS1 knockdown. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader 23. Compound 23 showed efficient SOS1 degradation in KRAS-driven cancer cells and achieved significant antiproliferative potency. Importantly, the combination of 23 with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRASG12C mutant cells in vitro and in vivo. Our findings demonstrated that KRASG12C inhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRASG12C inhibitor.

Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination

BackgroundLimited response to programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy is a major hindrance of checkpoint immunotherapy in non-small cell lung cancer (NSCLC). The abundance of PD-L1 on the...

Role of sex and sex hormones in PD-L1 expression in NSCLC: clinical and therapeutic implications.

Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy.

Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model.

Non-small cell lung cancer (NSCLC) is one of the most common cancers worldwide, and chemotherapy is one of its main treatment methods. However, there are significant differences in patients' reactions to chemotherapy, leading to unsatisfactory treatment outcomes. Therefore, identifying relevant factors that affect the efficacy of chemotherapy can help doctors better develop personalized treatment plans, improve the treatment effectiveness, and quality of life of patients. This article aims to understand the specific clinical role of CYP1B1 gene in NSCLC. Therefore, based on the individualized health model of CYP1B1 gene polymorphism, this article analyzes the prediction of postoperative chemotherapy efficacy for NSCLC. Through a study on the control variables of postoperative recovery of stage III NSCLC in a hospital, according to the findings of this study, 14 of the 32 patients in the EGFR mutation-positive group relapsed. In the EGFR-negative group, 13 of the 36 patients relapsed. It can be considered that CYP1B1 gene polymorphism has a good curative effect in postoperative chemotherapy of NSCLC, and it can effectively control the recurrence rate of cancer.

The influence of plasma sPD-L1 concentration on the effectiveness of immunotherapy in advanced NSCLC patients

IntroductionPD-L1 (Programmed Cell Death Ligand 1) is currently the only recognised marker of response to immunotherapy with anti-PD-1 or anti-PD-L1 antibodies in patients with advanced non-small cell lung cancer (NSCLC). However, this marker is not perfect. Soluble PD-L1 (sPD-L1) may be a novel predictor of immunotherapy efficacy in NSCLC patients.Material and methodsWe enrolled 120 patients (median age 68 ± 6.81 years, 70 males and 50 females) with locally advanced (stage IIIB; 10 patients) or advanced (stage IV; 110 patients) NSCLC. PD-L1 expression in tumour cells was assessed by immunohistochemistry (IHC) in 117 (97.5%) patients. The soluble PD-L1 concentration in plasma samples was measured using enzyme-linked immunosorbent assay (ELISA). The response to immunotherapy, progression-free survival (PFS), and overall survival (OS), calculated from the start of immunotherapy, were assessed in 119 patients.ResultsPatients with disease control had significantly lower (p = 0.0006) concentrations of sPD-L1 in blood plasma than patients with progression during the first months of immunotherapy or chemoimmunotherapy Patients with ≥ 6 month progression-free survival had a significantly higher (p = 0.013) percentage of tumor cells with PD-L1 expression than patients with shorter PFS. Patients with ≥ 6 months OS had significantly lower (p = 0.0142) plasma sPD-L1 concentrations than those with shorter overall survival. The median PFS was significantly higher in patients with low sPD-L1 concentrations than in those with high concentrations of this protein (5.8 vs. 2.5 months, HR = 0.6021, p = 0.0156). Similarly, patients with low sPD-L1 levels had a significantly higher median overall survival than those with sPD-L1 levels above the median (16.5 vs. 7 months, HR = 0.5354, p = 0.0071). There was no significant correlation between the percentage of tumour cells expressing PD-L1 and the concentration of sPD-L1 in the blood plasma.ConclusionHigh sPD-L1 concentration is a negative predictor of immunotherapy efficacy in patients with NSCLC. It is worthwhile to determine sPD-L1 concentration to predict the risk of resistance to anti-PD-1 or anti-PD-L1 antibodies with greater certainty.

RBM17 Expression Is Associated With the Efficacy of ICI Monotherapy in NSCLC With Low PD-L1 Expression.

Immune checkpoint inhibitors (ICIs) are currently a standard treatment tool for non-small cell lung cancer (NSCLC). RNA-binding motif protein 17 (RBM17), a splicing factor, is frequently over-expressed in NSCLC, but little is known about the role of RBM17 in the efficacy of ICIs for NSCLC. Thus, we investigated the correlation between RBM17 expression and ICI efficacy in NSCLC. Biopsy or surgical specimens were collected from patients with advanced or recurrent NSCLC who received ICI monotherapy or chemo-immunotherapy in a first-line setting. RBM17 expression was examined using immunohistochemistry. The correlation between the efficacy of ICI monotherapy or chemo-immunotherapy and RBM17 expression was evaluated. Among the 218 cases, 115 (52.8%) cases were positive for RBM17 expression. RBM17 expression was not associated with the objective response rate (ORR) or progression-free survival (PFS) in either of the ICI monotherapy or chemo-immunotherapy groups. However, among those with a low PD-L1 expression level (PD-L1 <50%; n=86), RBM17 expression was significantly associated with a better ORR (p=0.045) and a better PFS (p<0.001) in the ICI monotherapy group, and was significantly associated with a poor ORR in the chemo-immunotherapy group (p=0.041). RBM17 might be a useful predictive marker for a higher efficacy of ICI monotherapy in NSCLC patients with a low PD-L1 expression level.

Savolitinib: A Promising Targeting Agent for Cancer.

Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.

CERS4 predicts positive anti-PD-1 response and promotes immunomodulation through Rhob-mediated suppression of CD8+Tim3+ exhausted T cells in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the main malignant tumors with high mortality and short survival time. Immunotherapy has become the standard treatment for advanced NSCLC, but it has the problems of drug resistance and low response rate. Therefore, obtaining effective biomarkers to predict and enhance immune checkpoint inhibitors (ICIs) efficacy in NSCLC is important. Sphingolipid metabolism is recently found to be closely involved in tumor immunotherapy. CERS4, an important sphingolipid metabolizing enzyme, is positively correlated with the efficacy of anti-PD-1 therapy for NSCLC. Upregulation of CERS4 expression could improve the efficacy of anti-PD-1 therapy for NSCLC. High expression of CERS4 could downregulate the expression of Rhob in tumor. Significantly, the ratio of CD4+/CD8+ T cell increased and the ratio of Tim-3+/CD8+ T cell decreased in spleen and peripheral blood cells. When Rhob was knocked out, the efficacy of PD-1 mAb treatment increased, and the frequency of Tim-3+ CD8+ T cell decreased. This finding further confirmed the role of sphingolipid metabolites in regulating the immunotherapeutic function of NSCLC. These metabolites may improve the efficacy of PD-1 mAb in NSCLC by regulating the CERS4/Rhob/Tim-3 axis. Overall, this study provided a potential and effective target for predicting and improving the efficacy of ICIs for NSCLC. It also provided a new perspective for the study on the mechanisms of ICIs resistance for NSCLC.

Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells' resistance to anti-tumour drugs.

Background and aims: The outcomes of current treatment for non-small cell lung cancer (NSCLC) are unsatisfactory and development of new and more efficacious therapeutic strategies are required. The Notch pathway, which is necessary for cell survival to avert apoptosis, induces the resistance of cancer cells to antitumour drugs. Notch pathway activation is controlled by the cleavage of Notch proteins/receptors mediated by A disintegrin and metalloproteinase 17 (ADAM17); therefore, ADAM17 is a reliable intervention target for anti-tumour therapy to overcome the drug resistance of cancer cells. This work aims to develop and elucidate the activation of Compound 2b, a novel-structured small-molecule inhibitor of ADAM17, which was designed and developed and its therapeutic efficacy in NSCLC was assessed via multi-assays. Methods and results: A lead compound for a potential inhibitor of ADAM17 was explored via pharmacophore modelling, molecular docking, and biochemical screening. It was augmented by substituting two important chemical groups [R1 and R2 of the quinoxaline-2,3-diamine (its chemical skeleton)]; subsequently, serial homologs of the lead compound were used to obtain anoptimized compound (2b) with high inhibitory activity compared with leading compound against ADAM17 to inhibit the cleavage of Notch proteins and the accumulation of the Notch intracellular domain in the nuclei of NSCLC cells. The inhibitory activity of compound 2b was demonstrated by quantitative polymerase chain reaction and Western blotting. The specificity of compound 2b on ADAM17 was confirmed via point-mutation. Compound 2b enhanced the activation of antitumor drugs on NSCLC cells, in cell lines and nude mice models, by targeting the ADAM17/Notch pathway. Conclusion: Compound 2b may be a promising strategy for NSCLC treatment.

POTEE mutation as a potential predictive biomarker for immune checkpoint inhibitors in lung adenocarcinoma.

Precise selection of patients who could benefit from immune checkpoint inhibitors (ICIs) is an important challenge for immunotherapy in lung cancer. POTEE (POTE Ankyrin Domain Family Member E) is a member of one primate-specific gene family which have been identified as cancer-related antigens and potential target for immunotherapy of cancer. Here, we investigated the correlation between POTEE mutation and the clinical outcome of ICIs treatment in non-small cell lung cancer (NSCLC). We merged three NSCLC cohorts (n = 165) to assess predictive value of POTEE mutation of immunotherapy efficacy in NSCLC. The prognostic analysis and the potential molecular mechanism exploration were conducted based on the data from The Cancer Genome Atlas (TCGA) database. In the merged cohort, patients with POTEE-mutation (POTEE-Mut) had a significantly higher objective response rate (ORR) (100% vs 27.7%; P < 0.001) and longer progression-free survival (PFS) (P = 0.001; HR 0.08; 95% CI 0.01 - 0.54) compared to patients with POTEE wild-type (POTEE-WT) in NSCLC. Also, patients with POTEE-Mut showed higher ORR (100% vs 27.2%; P < 0.001) and longer PFS (P = 0.001; HR 0.07; 95% CI 0.01 - 0.52) in lung adenocarcinoma (LUAD). POTEE mutation was significantly associated with higher tumor mutational burden (TMB) and higher neoantigen load (NAL), but not with PD-L1 expression in LUAD. Gene set enrichment analyses (GSEA) analysis revealed prominent enrichment of signatures related to DNA repair in POTEE-Mut group (P < 0.001) in LUAD. Our results indicate that POTEE mutation could serve as a potential predictive biomarker for ICIs in LUAD. However, prospective cohort studies are still needed for further validation.

Preliminary efficacy and safety of camrelizumab plus metronomic oral vinorelbine as first-line therapy for people aged 70 and above with advanced non-small cell lung cancer (NSCLC) from a phase II trial.

e14677 Background: Traditional platinum-based combination chemotherapy used as the standard first‐line treatment for advanced NSCLC poses potential safety risk for patients (pts) aged 70 years and above. Moreover, data on immune checkpoint inhibitors treating older pts with lung cancer in the current pivotal trials is limited. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time. Compared with traditional chemotherapy, MCT shows better safety profile and antitumor angiogenesis and immunomodulatory effects. Camrelizumab, an anti-PD-1 inhibitor, demonstrated encouraging efficacy in NSCLC (CameL study and CameL-sq study). Here, we designed a phase II trial to evaluate the efficacy and safety of camrelizumab plus metronomic oral vinorelbine (mOV) as first-line therapy for Chinese older pts with advanced NSCLC. Methods: Key inclusion factors were pts aged 70 years and above, histologically or cytologically confirmed unresectable stage III and IV NSCLC without positive EGFR mutation, ALK fusions or ROS1 fusions, ECOG performance status 0-2, no previous systematic treatment. Pts received camrelizumab (200mg, D1, q3w) combined with mOV (30mg, tiw1, day 1-3-5 per week) for 6 cycles, followed by camrelizumab monotherapy maintenance until disease progression or intolerable side effects. The primary endpoint was progression free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: From March 2021 to November 2022, 12 pts were evaluable for inclusion in the study. The median age was 77 (range: 70-85) with 8 (67%) males. Median follow-up was 7.2 months (range 2.8 months-22.1 months). The median PFS was 9.3 months (95%CI: 3.9 months-14.7 months). The one-year OS rate was 66.3%. The ORR and DCR were 50% (95%CI: 25.4%-74.6%) and 83.3% (95%CI: 50.9%-90.1%), respectively. Pts with positive or negative PD-L1 responded similarly to the treatment (respectively at 5/8 and 1/2 on ORR). The median OS and DoR have not been reached. Adverse events (AEs) with any grade were observed in 10 (83.3%) pts, of which grade III-IV AEs were observed in 2 (16.7%) pts with neutropenia and interstitial pneumonia, respectively. Immune-related adverse events (irAEs) occurred in 3 (25%) pts, of which grade III-IV irAEs occurred in one (8.3%) patient with interstitial pneumonia. No grade 5 adverse event happened. Conclusions: The regimen of camrelizumab plus mOV for the first-line therapy for older NSCLC pts showed initial promising efficacy and safety profile, which suggests it is worth further exploration. Clinical trial information: ChiCTR2100049487 .

Safety, efficacy and biomarker data in patients with non-small cell lung cancer treated with the anti-IL1RAP antibody nadunolimab in combination with platinum doublet.

9089 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP), expressed in various tumors, is essential for IL-1α and IL-1β signaling. IL-1α/IL-1β are implicated in tumor progression and therapy resistance, and chemotherapy can upregulate IL-1α in e.g. non-small cell lung cancer (NSCLC). Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α/IL-1β signaling. Here, data are reported from clinical phase 1/2 trials in NSCLC pts given nadunolimab and platinum doublet. Methods: Pts with advanced NSCLC, 1st line or progressed on pembrolizumab, received nadunolimab at 1 (n=16), 2.5 (n=3) or 5 mg/kg (n=11) with cisplatin/gemcitabine (NCG), or at 2.5 mg/kg with carboplatin/pemetrexed (NCP) (n=5). Four additional pts, 3rd line or beyond, received NCG at 1 or 1.75 mg/kg nadunolimab. Primary objective was safety; efficacy was evaluated as a secondary objective and effects on serum and tumor tissue biomarkers explored. Results: The 30 1st or 2nd line pts given NCG had a median PFS of 7.2 months (95% CI 5.5-8.2), ORR of 53% (34-72) and DoR of 5.8 months (3.7-7.5). A dose-response trend was observed for PFS and DoR (Table). Twenty non-progressing pts continued nadunolimab as monotherapy post chemo; 8 of these remained in disease control for a further 12-131 wks. Nadunolimab monotherapy was well tolerated with ≥grade 3 adverse events reported less frequently. Two pts (non-squamous, 2nd line post pembrolizumab) showed complete responses, one observed after &gt;40 wks of nadunolimab monotherapy. Furthermore, confirmed partial responses were observed in 3 of 5 pts given NCP, and 2 of 4 3rd line or beyond pts given NCG. NCG reduced several serum markers, e.g. CRP and tumor-promoting HGF, effects which were maintained by nadunolimab monotherapy. Additionally, a decrease of MCP-3 and 4 was observed during monotherapy. NCG also reduced IL-1- and tumor microenvironment (TME)-related markers in serum (angiopoietin 1, CXCL5, IL-8, TWEAK and VEGFA). Spatial analyses of protein and RNA markers in tumor biopsies are ongoing to verify potential effects in the TME. Conclusions: NCG shows promising efficacy in NSCLC with a trend for dose response, and long-term disease control by nadunolimab monotherapy post chemo with good safety. These observations are supported by changes in TME-related serum biomarkers. Preliminary data suggest similar efficacy with NCP, and in more heavily pretreated pts. Clinical trial information: NCT03267316 , NCT05116891 . [Table: see text]

Dipeptidyl peptidase 4 inhibitor reduces tumor-associated macrophages and enhances anti-PD-L1-mediated tumor suppression in non-small cell lung cancer

PurposeThe efficacy of immune checkpoint inhibitors such as programmed cell death ligand 1 (PD-L1) antibodies in non-small cell lung cancer (NSCLC) is limited, and combined use with other therapies is recommended. Dipeptidyl peptidase 4 (DPP4) inhibitors, a class of small molecule inhibitors, are highly effective for treating type 2 diabetes. Emerging evidence implicates DPP4 inhibitors as immunomodulators that modify aspects of innate and adaptive immunity. We evaluated the combination of a DPP4 inhibitor (anagliptin) and PD-L1 blockade in an NSCLC mouse model.MethodsThe effect of the combination of anti-PD-L1 and anagliptin was evaluated in subcutaneous mouse models of NSCLC. Tumor-infiltrating immune cells were analyzed by flow cytometry. Bone marrow-derived monocytes of C57BL/6 mice were isolated in vitro to examine the underlying mechanism of anagliptin on the differentiation and polarization of macrophage.ResultsAnagliptin dramatically improved the efficacy of PD-L1 antibody monotherapy by inhibiting macrophage formation and M2 polarization in the tumor microenvironment. Mechanistically, anagliptin suppressed the production of reactive oxygen species in bone marrow monocytes by inhibiting NOX1 and NOX2 expression induced by macrophage colony-stimulating factor, reduced late ERK signaling pathway activation, and inhibited monocyte-macrophage differentiation. However, the inhibitory effect was reactivated by lipopolysaccharide and interferon-gamma interacting with corresponding receptors during M1 macrophage polarization, but not M2.ConclusionsAnagliptin can enhance PD-L1 blockade efficacy in NSCLC by inhibiting macrophage differentiation and M2 macrophage polarization, and combination therapy may be a promising strategy for treating PD-L1 blockade therapy-resistant patients with NSCLC.