ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages.

BACKGROUND: Understanding the mechanisms that mediate the interaction between tumor and immune cells may provide therapeutic benefit to patients with cancer. The N6-methyladenosine (m6A) demethylase, ALKBH5 (alkB homolog 5), is overexpressed in non-small cell lung cancer. However, its role in the tumor microenvironment is unknown. METHODS: Datasets and tissue samples were used to determine the relationship between ALKBH5 expression and immunotherapy efficacy. Bioinformatic analysis, colorimetric assay to determine m6A RNA methylation, dual luciferase reporter assay, RNA/m6A-modified RNA immunoprecipitation, RNA stability assay, and RNA sequencing were used to investigate the regulatory mechanism of ALKBH5 in non-small cell lung cancer. In vitro and in vivo assays were performed to determine the contribution of ALKBH5 to the development of non-small cell lung cancer. RESULTS: ALKBH5 was upregulated in primary non-small cell lung cancer tissues. ALKBH5 was positively correlated with programmed death-ligand 1 expression and macrophage infiltration and was associated with immunotherapy response. JAK2 was identified as a target of ALKBH5-mediated m6A modification, which activates the JAK2/p-STAT3 pathway to promote non-small cell lung cancer progression. ALKBH5 was found to recruit programmed death-ligand 1-positive tumor-associated macrophages and promote M2 macrophage polarization by inducing the secretion of CCL2 and CXCL10. ALKBH5 and tumor-associated macrophage-secreted IL-6 showed a synergistic effect to activate the JAK2/p-STAT3 pathway in cancer cells. CONCLUSIONS: ALKBH5 promotes non-small cell lung cancer progression by regulating cancer and tumor-associated macrophage behavior through the JAK2/p-STAT3 pathway and the expression of CCL2 and CXCL10, respectively. These findings suggest that targeting ALKBH5 is a promising strategy of enhancing the anti-tumor immune response in patients with NSCLC and that identifying ALKBH5 status could facilitate prediction of clinical response to anti-PD-L1 immunotherapy.

Efficacy and safety of anti-PD-1/PD-L1-based dual immunotherapies versus PD-1/PD-L1 inhibitor alone in patients with advanced solid tumor: a systematic review and meta-analysis.

INTRODUCTION: Numerous randomized controlled trials (RCTs) have investigated PD-1/PD-L1 inhibitor-based combination therapies. The debate surrounding the potential additive clinical benefits of combination of two immune-oncology (IO) therapies for cancer patients persists. METHODS: Both published and grey sources of randomized clinical trials that compared anti-PD-1/PD-L1-based immunotherapy combinations with monotherapy in patients with advanced or metastatic solid tumors were encompassed. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: Our analysis encompassed 31 studies comprising 10,341 patients, which covered 12 distinct immune-oncology combination regimens. Across all patients, the immunotherapy combinations exhibited the capability to enhance the ORR (OR = 1.23 [95% CI 1.13-1.34]) and extend PFS (HR = 0.91 [95% CI 0.87-0.95]). However, the observed enhancement in OS (HR = 0.96 [95% CI 0.91-1.01]) was of no significance. Greater benefits in terms of PFS (HR = 0.82 [95% CI 0.72 to 0.93]) and OS (HR = 0.85 [95% CI 0.73 to 0.99]) may be particularly pronounced in cases where PD-L1 expression is negative. Notably, despite a heightened risk of any-grade TRAEs (OR = 1.72 [95% CI 1.40-2.11]) and grade greater than or equal to 3 TRAEs (OR = 2.01 [95% CI 1.67-2.43]), toxicity was generally manageable. CONCLUSIONS: This study suggests that incorporating an additional immunotherapy agent with PD-1/PD-L1 inhibitors can elevate the response rate and reduce the risk of disease progression, all while maintaining manageable toxicity. However, there remains a challenge in translating these primary clinical benefits into extended overall survival.

A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer.

Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy. Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity. This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8+ TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN-α-stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8+ T cells. Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.

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.

STING mediates LPS-induced acute lung injury by regulating ferroptosis.

The pathogenesis of acute lung injury is not fully understood. Stimulator of interferon genes (STING) and ferroptosis have been implicated in various pathological and physiological processes, including acute lung injury (ALI). However, the relationship between STING and ferroptosis in lipopolysaccharide (LPS)-induced ALI is unclear. We found that LPS stimulation activated STING and ferroptosis. Furthermore, STING knockout and ferroptosis inhibitor alleviated lung inflammation and epithelial cell damage. Also, STING knockout reduced inflammation injury and ferroptosis. Notably, the ferroptosis inducer reversed the alleviation of inflammation caused by STING knockout. These results show that STING participates in the inflammation injury of ALI by regulating ferroptosis. Results also showed that p-STAT3 levels increased after STING knockout, suggesting that STING negatively regulates STAT3 activation. Besides, STAT3 inhibitor aggravated ferroptosis after STING knockout, indicating that STING regulates ferroptosis through STAT3 signaling. In conclusion, STING mediates LPS-induced ALI by regulating ferroptosis, indicating that STING and ferroptosis may be new targets for ALI treatment.

Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study.

Background: The prognosis of small cell lung cancer (SCLC) patients is poor, and the standard first-line treatment for limited-stage small cell lung cancer (LS-SCLC) is still chemotherapy and thoracic radiotherapy. The primary objectives of our study were to confirm the superior efficacy of first-line immune checkpoint inhibitors (ICIs) plus etoposide and platinum (EP) for LS-SCLC and find crucial biomarkers. Methods: We analyzed LS-SCLC patients from three medical centers, employing propensity score matching for group comparability. Survival outcomes were estimated by Kaplan-Meier and Cox regression analyses. Additionally, we conducted univariate and multivariate analyses to investigate potential predictive factors. Results: Among 150 patients in our study, we successfully matched 41 pairs. The median overall survival (OS) was 29.5 months in the EP + ICIs group and 20.0 months in the EP group {hazard ratio (HR) =0.64 [95% confidence interval (CI): 0.41-1.02], P=0.059}. The median progression-free survival (PFS) was significantly extended in the EP + ICIs group (14.6 months), compared to the EP group (8.6 months) [HR =0.42 (95% CI: 0.28-0.63), P<0.001]. After matching, patients receiving chemo-immunotherapy had a median OS of 36.1 months, significantly surpassing those receiving chemotherapy alone (19.0 months) [HR =0.51 (95% CI: 0.28-0.93), P=0.02]. And the patients in the EP + ICIs group also had longer PFS after matching [HR =0.42 (95% CI: 0.25-0.71), P=0.001]. No significant difference in the objective response rate (ORR) and treatment-related adverse events (trAEs) between the two groups was found (ORR: EP: 81.0%, EP + ICIs: 90.0%, P=0.14; trAEs: EP: grade 1-2, 49.3%; grade 3-4, 42.5%; EP + ICIs: grade 1-2, 40.0%; grade 3-4, 49.1%, P=0.62). The multivariate analysis presented that the history of immunotherapy [EP + PD-1 inhibitors: HR =0.33 (95% CI: 0.17-0.62), P=0.001; EP + PD-L1 inhibitors: HR =0.18 (95% CI: 0.06-0.60), P=0.005] and baseline lung immune prognostic index (LIPI) [intermediate: HR =2.22 (95% CI: 1.20-4.13), P=0.01; poor: HR =2.03 (95% CI: 0.71-5.77), P=0.18] were independent prognostic factors for PFS among all LS-SCLC cases. However, no independent prognostic factor was identified for OS. Conclusions: Our real-world data showed promising clinical efficacy and tolerable safety of first-line programmed cell death protein 1 (PD-1) inhibitors or programmed cell death ligand 1 (PD-L1) inhibitors in cases with LS-SCLC. Additionally, LIPI may serve as a valuable prognostic factor.

Comparative efficacy and safety of COVID-19 vaccines in phase III trials: a network meta-analysis.

BACKGROUND: Over a dozen vaccines are in or have completed phase III trials at an unprecedented speed since the World Health Organization (WHO) declared COVID-19 a pandemic. In this review, we aimed to compare and rank these vaccines indirectly in terms of efficacy and safety using a network meta-analysis. METHODS: We searched Embase, MEDLINE, and the Cochrane Library for phase III randomized controlled trials (RCTs) from their inception to September 30, 2023. Two investigators independently selected articles, extracted data, and assessed the risk of bias. Outcomes included efficacy in preventing symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the incidence of serious adverse events (SAEs) according to vaccine type and individual vaccines in adults and elderly individuals. The risk ratio and mean differences were calculated with 95% confidence intervals using a Bayesian network meta-analysis. RESULTS: A total of 25 RCTs involving 22 vaccines were included in the study. None of vaccines had a higher incidence of SAEs than the placebo. Inactivated virus vaccines might be the safest, with a surface under the cumulative ranking curve (SUCRA) value of 0.16. BIV1-CovIran showed the highest safety index (SUCRA value: 0.13), followed by BBV152, Soberana, Gam-COVID-Vac, and ZF2001. There were no significant differences among the various types of vaccines regarding the efficacy in preventing symptomatic SARS-CoV-2 infection, although there was a trend toward higher efficacy of the mRNA vaccines (SUCRA value: 0.09). BNT162b2 showed the highest efficacy (SUCRA value: 0.02) among the individual vaccines, followed by mRNA-1273, Abdala, Gam-COVID-Vac, and NVX-CoV2373. BNT162b2 had the highest efficacy (SUCRA value: 0.08) in the elderly population, whereas CVnCoV, CoVLP + AS03, and CoronaVac were not significantly different from the placebo. CONCLUSIONS: None of the different types of vaccines were significantly superior in terms of efficacy, while mRNA vaccines were significantly inferior in safety to other types. BNT162b2 had the highest efficacy in preventing symptomatic SARS-CoV-2 infection in adults and the elderly, whereas BIV1-CovIran had the lowest incidence of SAEs in adults.

Efficacy of immunotherapy in patients with oncogene-driven non-small-cell lung cancer: a systematic review and meta-analysis.

Background: Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced non-small-cell lung cancer (NSCLC). However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene-positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC and concluded the efficacy of altered subtypes. Methods: A literature search was performed using PubMed, Web of Science, and Cochrane databases. The primary endpoints included the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients with oncogene-driven NSCLC. Results: In all, 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORRs in clinical trials treated with monoimmunotherapy of EGFR, ALK, and KRAS alteration were 6%, 0%, and 23%, respectively. In retrospective studies, the pooled ORRs of EGFR, ALK, KRAS, BRAF, MET, HER2, RET, and ROS1 alteration were 8%, 3%, 28%, 24%, 23%, 14%, 7%, and 8%, respectively. Among them, the pooled ORRs of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping, and MET-amplification were 33% 40%, 20%, 34%, 17%, and 60%, respectively. In addition, the pooled mPFS rates of EGFR, KRAS, MET, HER2, and RET alteration were 2.77, 3.24, 2.48, 2.31, and 2.68 months, while the pooled mOS rates of EGFR and KRAS alteration were 9.98 and 12.29 months, respectively. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. Conclusions: EGFR-, ALK-, HER2-, RET-, and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation, and MET amplification have better responses to immunotherapy, and more prospective studies are needed for further research.

Efficacy of immunotherapy in patients with oncogene-driven non-small cell lung cancer: a systematic review and meta analysis Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced NSCLC. However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC, and concluded the efficacy of altered subtypes. 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORR in clinical trials treated with monoimmunotherapy was of EGFR, ALK and KRAS alteration was 6%, 0%, and 23%, respectively. While in retrospective studies, the pooled ORR of EGFR, ALK, KRAS, BRAF, MET, HER2, RET and ROS1 alteration was 8%, 3%, 28%, 24%, 23%, 14%, 7% and 8%, respectively. Among them, the pooled ORR of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping and MET-amplification was 33% 40%, 20%, 34%, 17% and 60%, respectively. Additionally, the pooled mPFS of EGFR, KRAS, MET, HER2 and RET alteration was 2.77, 3.24, 2.48, 2.31 and 2.68 months, while the pooled mOS of EGFR and KRAS alteration was 9.98 and 12.29 months. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) was reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. EGFR, ALK, HER2, RET and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy, but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation and MET amplification have better response to immunotherapy, and more prospective studies are needed for further research.

The safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in non-small cell lung cancer patients with oncogenic alterations.

Background: The anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunotherapy has been extensively used in patients with non-small cell lung cancer (NSCLC) in which the tumors are negative for oncogenic alterations. However, whether PD-1/PD-L1 blockade therapy could be applicable in patients harboring oncogenic mutations is largely unknown. Methods: In this retrospective study, we analyzed the safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in a NSCLC cohort of 84 patients who harbored oncogenic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), k-Ras, RET, HER2 and BRAF. The patients were followed up till disease progression or death. The adverse effects associated with the treatment were carefully evaluated and timely interrupted. Results: There were 50 patients harboring EGFR mutations, 17 patients with k-Ras mutation, 2 patients with ALK rearrangement, 6 patients with RET rearrangement, 6 patients with HER2 exon20 insertion and 3 patients with BRAF V600E mutation. About 58.8% of the k-Ras mutant patients responded to the combinational treatment. The median progression-free survival (mPFS) of the k-Ras cohort was 14 months, with the 12-month median overall survival (mOS) ratio and the 24-month OS ratio of 86.7% and 75.8%, respectively. Patients with EGFR exon21 L858R mutation or RET rearrangement tended to have a more favorable response, while patients harboring ALK rearrangement, HER2 exon20 insertion and BRAF V600E mutation did not respond well to anti-PD-1 inhibitor-based combinational therapy. The incidence of treatment-related toxicity was 52.3% and the most common immune-related adverse events (irAEs) were PD-1 inhibitors-related hypothyroidism and pneumonitis. The PD-L1 status and lung immune prognostic index (LIPI) could be used as biomarkers dictating therapeutic outcomes of the combinational therapy. Conclusions: The anti-PD-1 inhibitor-based combinational therapy elicited exciting anti-tumor efficacy and prolonged patient survival with manageable adverse effects in NSCLC patients harboring oncogenic alterations. The PD-L1 status and LIPI could be used as a biomarker predicting response to anti-PD-1 inhibitor-based combinational treatment in these patients.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Utilizing metagenomic next-generation sequencing for pathogen detection and diagnosis in lower respiratory tract infections in real-world clinical practice.

BACKGROUND: Infectious etiologies of lower respiratory tract infections (LRTIs) by the conventional microbiology tests (CMTs) can be challenging. Metagenomic next-generation sequencing (mNGS) has great potential in clinical use for its comprehensiveness in identifying pathogens, particularly those difficult-to-culture organisms. METHODS: We analyzed a total of 205 clinical samples from 201 patients with suspected LRTIs using mNGS in parallel with CMTs. mNGS results were used to guide treatment adjustments for patients who had negative CMT results. The efficacy of treatment was subsequently evaluated in these patients. RESULTS: mNGS-detected microorganisms in 91.7% (188/205) of the clinical samples, whereas CMTs demonstrated a lower detection rate, identifying microorganisms in only 37.6% (77/205) of samples. Compared to CMT results, mNGS exhibited a detection sensitivity of 93.5% and 95.4% in all 205 clinical samples and 180 bronchoalveolar lavage fluid (BALF) samples, respectively. A total of 114 patients (114/201; 56.7%) showed negative CMT results, among which 92 received treatment adjustments guided by their positive mNGS results. Notably, 67.4% (62/92) of patients demonstrated effective treatment, while 25% (23/92) experienced a stabilized condition. Subgroup analysis of cancer patients revealed that 41.9% (13/31) exhibited an effective response to treatment, and 35.5% (11/31) maintained a stable condition following medication adjustments guided by mNGS. CONCLUSION: mNGS demonstrated great potential in identifying microorganisms of clinical significance in LRTIs. The rapid turnaround time and reduced susceptibility to the impact of antimicrobial administration make mNGS a valuable supplementary tool for diagnosis and treatment decision-making for suspected LRTIs in clinical practice.

A Narrative Review: The Role of NETs in Acute Respiratory Distress Syndrome/Acute Lung Injury.

Nowadays, acute respiratory distress syndrome (ARDS) still has a high mortality rate, and the alleviation and treatment of ARDS remains a major research focus. There are various causes of ARDS, among which pneumonia and non-pulmonary sepsis are the most common. Trauma and blood transfusion can also cause ARDS. In ARDS, the aggregation and infiltration of neutrophils in the lungs have a great influence on the development of the disease. Neutrophils regulate inflammatory responses through various pathways, and the release of neutrophils through neutrophil extracellular traps (NETs) is considered to be one of the most important mechanisms. NETs are mainly composed of DNA, histones, and granuloproteins, all of which can mediate downstream signaling pathways that can activate inflammatory responses, generate immune clots, and cause damage to surrounding tissues. At the same time, the components of NETs can also promote the formation and release of NETs, thus forming a vicious cycle that continuously aggravates the progression of the disease. NETs are also associated with cytokine storms and immune balance. Since DNA is the main component of NETs, DNase I is considered a viable drug for removing NETs. Other therapeutic methods to inhibit the formation of NETs are also worthy of further exploration. This review discusses the formation and mechanism of NETs in ARDS. Understanding the association between NETs and ARDS may help to develop new perspectives on the treatment of ARDS.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Clinical definition of secondary resistance to immunotherapy in non-small cell lung cancer.

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Safety and efficacy of thoracic radiotherapy combined with chemo-immunotherapy in patients with extensive-stage small cell lung cancer: a multicenter retrospective analysis.

Background: Immunotherapy has greatly increased the survival time of patients with extensive-stage small cell lung cancer (ES-SCLC), and is now a standard first-line treatment for these patients. Increasing evidence suggests a possible synergistic effect between immunotherapy and radiotherapy, yet there is a paucity of evidence regarding the efficacy and safety of thoracic radiotherapy (TRT) combined with chemo-immunotherapy for ES-SCLC. Methods: The medical records of 78 consecutive patients with ES-SCLC who received TRT in combination with chemo-immunotherapy at Jinling Hospital and Jiangsu Cancer Hospital from January 2019 to January 2023 were retrospectively reviewed. The median overall survival (mOS) time and median progression-free survival (mPFS) time were used to evaluate efficacy, and the incidence of adverse events (AEs) was used to evaluate safety. Results: The median follow-up time was 31.9 months, the objective response rate (ORR) was 59%, and the disease control rate (DCR) was 89.8%. The mOS time was 20.0 months, and the 6-month OS rate was 95%. The mPFS time was 9.2 months, and the 6-month PFS rate was 78%. There were no treatment-related deaths. The incidence of pneumonitis was 23.1%, the incidence of radiation esophagitis was 5.1%, and 2 patients experienced high-grade pneumonitis. Primary liver metastasis was a predictor of poor OS and PFS. Patients who received consolidative TRT after chemo-immunotherapy experienced more benefit than those who received TRT as palliative or salvage treatment for superior vena cava syndrome or disease progression. Conclusions: TRT is a feasible treatment for patients who receive chemo-immunotherapy for the management of ES-SCLC in consideration of its considerable efficacy and tolerable safety risk. This treatment is especially useful for patients without primary liver metastasis and who receive consolidative TRT after chemo-immunotherapy. Large-scale prospective studies are needed to confirm the efficacy and safety of this treatment modality.

Efficacy and safety of first-line PD-1/PD-L1 inhibitor combinations for extensive-stage small-cell lung cancer: a Bayesian network meta-analysis.

Objectives: Several randomized controlled trials (RCTs) indicated that first-line programmed cell death protein-1/death-ligand 1 inhibitors plus chemotherapy (PD-1/PD-L1 + chemo) led to survival benefits in extensive-stage small-cell lung cancer (ES-SCLC) compared with platinum-based chemotherapy. This study aims to identify the optimal PD-1/PD-L1 + chemo combination strategy. Methods: We included RCTs comparing PD-1/ PD-L1 + chemo versus chemo alone in ES-SCLC. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ⩾3 treatment-related adverse events were considered. Odds ratios (ORs), hazard ratios (HRs), and their 95% confidence intervals (CIs) were extracted. Results: Six RCTs with 2600 patients were analyzed in this Bayesian network meta-analysis. Results showed that adding PD-1/PD-L1 inhibitors to chemotherapy led to significant benefits in OS (HR = 0.72, 95% CI: 0.66-0.79), PFS (HR = 0.69, 95% CI: 0.63-0.75), and ORR (OR = 1.32, 95% CI: 1.12-1.56), and no differences in toxicity were found (OR = 1.09, 95% CI: 0.92-1.30). Serplulimab plus chemotherapy was found to provide the best OS (HR = 0.63, 95% CI: 0.49-0.82), the best PFS (HR = 0.47, 95% CI: 0.38-0.59), and the best ORR (OR = 1.7, 95% CI: 1.15-2.53). Moreover, although there were no difference between PD-L1 + chemo and PD-1 + chemo regarding OS (HR = 0.99, 95% CI: 0.91-1.08) and ORR (OR = 1.27, 95% CI: 0.91-1.78), PD-1 + chemo showed a significant benefit in PFS (HR = 0.82, 95% CI: 0.68-0.98) compared with PD-L1 + chemo. Conclusions: Serplulimab plus chemotherapy seems to be superior first-line immunotherapy combination for patients with ES-SCLC. PD-1 + chemo seems to outperform PD-L1 + chemo in PFS.

Risk factors for symptomatic malignant pleural effusion recurrence in patients with actionable mutations in advanced lung adenocarcinoma.

Background: Malignant pleural effusion (MPE) comes generally with high mortality and poor prognosis. Recurrence of symptomatic MPE is always accompanied by poor survival quality. In lung adenocarcinoma, researchers speculate whether patients with actionable mutation or without are applicable to different management models for MPE. Under the background of the high mutation probability and the encouraging therapeutic response in Asians, researches on the risk factors of MPE are in need. Methods: This retrospective review included 343 metastatic lung adenocarcinoma patients with MPE. Recurrence was defined as recurrent symptomatic MPE requiring the second thoracentesis to relieve symptoms within 300 days after the first thoracentesis. Univariable and multivariable Cox regression analysis were utilized to investigate independent risk factors for MPE recurrence. Results: Of the 343 patients involved, 139 experienced MPE recurrence within 300 days; 34.3% in 201 patients with actionable mutations and 51.2% in 129 patients without actionable mutations are in the recurrence. The median recurrence-free survival (RFS) of the group without mutations was 161 days. The median RFS of the other group with mutations was 300 days. Patients with actionable mutations showed a significantly lower hazard of MPE recurrence on univariate analysis. The multivariate analysis indicated that receiving targeted therapy after the first thoracentesis within 30 days, lower neutrophil-to-lymphocyte ratio (NLR) level, lower serum lactate dehydrogenase (s-LDH) level, and lower serum carcinoembryonic antigen (s-CEA) level were independent protective factors. In subgroup analysis, risk factors differed. Receiving targeted therapy after the first thoracentesis within 30 days remained an independent factor in the mutated patients. Conclusions: The findings herein indicated the characteristics of specific patients at high risk for MPE recurrence in lung adenocarcinoma. Patients with actionable mutations benefit more in MPE recurrence and could benefit from targeted therapy and active intrapleural management.

Zebrafish in Lung Cancer Research.

Zebrafish is increasingly used as a model organism for cancer research because of its genetic and physiological similarities to humans. Modeling lung cancer (LC) in zebrafish has received significant attention. This review focuses on the insights gained from using zebrafish in LC research. These insights range from investigating the genetic and molecular mechanisms that contribute to the development and progression of LC to identifying potential drug targets, testing the efficacy and toxicity of new therapies, and applying zebrafish for personalized medicine studies. This review provides a comprehensive overview of the current state of LC research performed using zebrafish, highlights the advantages and limitations of this model organism, and discusses future directions in the field.

Tandem CAR-T cells targeting MUC1 and PSCA combined with anti-PD-1 antibody exhibit potent preclinical activity against non-small cell lung cancer.

Chimeric antigen receptor (CAR)-T cells encounter many issues when treating solid tumors, including tumor antigen heterogeneity and immunosuppression. United targeting of two tumor-associated antigens (TAAs) and blocking of PD-1 may solve this problem and enhance the function of CAR-T. Mucin 1 (MUC1) and prostate stem cell antigen (PSCA) are overexpressed in non-small cell lung cancer (NSCLC). Here, we constructed a bivalent tandem CAR-T (Tan CAR-T), which can simultaneously target MUC1 and PSCA and evaluated its effects of inhibiting non-small cell lung cancer (NSCLC) in vitro and in vivo. Results indicated that the tumor killing effect of these Tan CAR-T was more effective than that of single-target CAR-T, its antitumor efficacy could be further strengthened by anti-PD-1 antibody. Our study reported a previously unstudied therapeutic effect of a Tan CAR-T in NSCLC, providing a preclinical rationale for anti-PD-1 antibody combined with Tan CAR-T targeting MUC1 and PSCA in the treatment of NSCLC.

Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China.

The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell-surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non-small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second-generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first-generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET-targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.