Immunotherapy In Non-small Cell Lung Cancer Research Articles

Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer

BackgroundCurrent evidence underlines the active role of neural infiltration and axonogenesis within the tumor microenvironment (TME), with implications for tumor progression. Infiltrating nerves stimulate tumor growth and dissemination by secreting neurotransmitters, whereas tumor cells influence nerve growth and differentiation through complex interactions, promoting tumor progression. However, the role of neural infiltration in the progression of non-small cell lung cancer (NSCLC) remains unclear.MethodsThis study employs the techniques of immunohistochemistry, immunofluorescence, RNA sequencing, molecular biology experiments, and a murine orthotopic lung cancer model to deeply analyze the specific mechanisms behind the differential efficacy of NSCLC immunotherapy from the perspectives of neuro-tumor signal transduction, tumor metabolism, and tumor immunity.ResultsThis study demonstrates that nerve growth factor (NGF) drives neural infiltration in NSCLC, and 5-hydroxytryptamine (5-HT), which is secreted by nerves, is significantly elevated in tumors with extensive neural infiltration. Transcriptome sequencing revealed that 5-HT enhanced glycolysis in NSCLC cells. Pathway analysis indicated that 5-HT activated the PI3K/Akt/mTOR pathway, promoting tumor metabolic reprogramming. This reprogramming exacerbated immunosuppression in the TME. Neutralizing 5-HT-mediated metabolic reprogramming in tumor immunity enhanced the efficacy of PD-1 monoclonal antibody treatment in mice.ConclusionsThe findings of this study provide a novel perspective on the crosstalk between nerves and lung cancer cells and provide insights into further investigations into the role of nerve infiltration in NSCLC progression.

Ultrasound-Responsive Nanocarriers Delivering siRNA and Fe3O4 Nanoparticles Reprogram Macrophages and Inhibit M2 Polarization for Enhanced NSCLC Immunotherapy.

Lung cancer has emerged as the second most common type of malignant tumor worldwide, and it has the highest mortality rate. The overall 5-year survival rate stands at less than 20%, which is primarily related to the limited therapeutic options and the complexity of the tumor immune microenvironment. In the tumor microenvironment, M1 macrophages are known for their tumor-killing capabilities. Although they are less numerous, they play an important role in tumor immunity. Therefore, increasing M1 macrophages' presence is considered a strategy to enhance targeted phagocytosis and antitumor efficacy in nonsmall cell lung cancer (NSCLC). This study introduces the development of folic acid (FA)-conjugated liposomal nanobubbles for precise delivery of PFH, STAT3 siRNA, and Fe3O4 to the tumor microenvironment. These encapsulated PFH liposomal nanobubbles exhibit significant visualization potential and underwent phase transition when exposed to low-intensity focused ultrasound (LIFU). The release of Fe3O4 activates the IRF5 signaling pathway, converting M2-like macrophages to M1. In addition, STAT3 siRNA effectively interrupts the JAK-STAT3 pathway, inhibiting the polarization of M2-like macrophages in tumor-associated macrophages (TAMs). This dual-action therapy facilitates T-cell activation and proliferation, thereby enhancing the immune response against NSCLC.

Ultrasound-responsive nanocarriers with siRNA and Fe3O4 regulate macrophage polarization and phagocytosis for augmented non-small cell lung cancer immunotherapy

The immunosuppressive tumor microenvironment (TME) significantly inhibits the effective anti-tumor immune response, greatly affecting the efficacy of immunotherapy. Most tumor-associated macrophages (TAMs) belong to the M2 phenotype, which contributes significantly to the immunosuppressive effects in non-small cell lung cancer (NSCLC) TME. The interaction between signal regulatory protein α (SIRPα) expressed on macrophages and CD47, a transmembrane protein overexpressed on cancer cells, activates the "eat-me-not" signaling pathway, inhibiting phagocytosis. In this study, a folic acid (FA)-modified ultrasound responsive gene/drugs delivery system, named FA@ PFP @ Fe3O4 @LNB-SIRPα siRNA (FA-PFNB-SIRPα siRNA), was developed using 1,2-dioleoacyl-3-trimethylammonium-propane (DOTAP), FA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol)2000] (DSPE-PEG2000-FA), cholesterol, and perfluoropentane (PFP), for the delivery of siRNA encoding SIRPα mRNA and immune adjuvant Fe3O4 nanoparticles. Under ultrasound conditions, the nanobubbles effectively transfected macrophages, inhibiting SIRPα mRNA and protein expression, promoting the phagocytosis of TAMs, and synergistically reversing M2 polarization. This system promotes the infiltration of T cells, enhances the proliferation and activation of cytotoxic T cells, and inhibits the infiltration of immunosuppressive cells in tumor tissues. Administration of FA-PFNB-SIRPα siRNA combined with ultrasound significantly inhibits NSCLC progression. The study highlights the potential of ultrasound nanotechnology-enabled delivery of SIRPα siRNA and Fe3O4 as an effective strategy for macrophage-based immunotherapy to reshape the immunosuppressive TME for cancer therapy.Graphical

12337 Nivolumab Induced Secondary Adrenal Insufficiency And Hypothyroidism In A Patient With Graves’ Disease: A Case Report

Abstract Disclosure: F. Sajid: None. J. Kaur: None. A. Zatsepina: None. M. Khan: None. C.A. Resta: None. Introduction: We present a case of a patient with Graves’ disease who developed concurrent secondary adrenal insufficiency (SAI) and primary hypothyroidism while undergoing treatment with nivolumab for non-small cell lung cancer (NSCLC). This case sheds light on the immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy. Case Presentation: A 63-year-old woman with a history of Graves’ disease and NSCLC undergoing neoadjuvant chemoimmunotherapy was admitted with hyponatremia. She was diagnosed with Graves’ disease a year before and was treated with methimazole (MMI). When she was diagnosed with Graves’ disease, her TSI was 1.64 IU/L (<0.55). Before starting nivolumab, TSH had normalized at 0.5 MCIU/mL on MMI therapy. She started nivolumab 3 months before admission. One month after starting nivolumab, her TSH was <0.01. By the time she was admitted, she had severe hypothyroidism and SAI with sodium 116 mmol/L (135-149), TSH 40.34 mIU/mL (0.39-4.08), free T4 <0.25 ng/dL (0.8-1.8), TSI 21.2 IU/L (0.00-0.55) Total Cortisol 0.4 ug/dL (6.7-27.6), AM Cortisol 0.6 ug/dL, ACTH <1.5 pg/mL (7.2-63.3), LH 75.5 IU/L (7.7-58.5), and FSH 179 IU/L (25.8-134.8). MMI was discontinued due to hypothyroidism. She was started on replacement therapy with levothyroxine and hydrocortisone. Subsequent sodium levels normalized. Discussion: Nivolumab has emerged as a promising immunotherapy for NSCLC. Our patient developed irAEs following nivolumab treatment. Notably, this case represents only the third documented case to our knowledge of both primary hypothyroidism and secondary adrenal insufficiency occurring post-nivolumab treatment. Workup for our patient revealed two irAE’s. She developed primary hypothyroidism and isolated ACTH deficiency with other pituitary function remaining normal. The pattern of thyroid profile over time was consistent with thyroiditis due to ICI therapy. TSI increased, ruling out remission from Graves’ disease. Even after discontinuing methimazole, she remained hypothyroid. Hence, in this case, ICI effectively acted as definitive therapy for her Graves’ disease. Conclusion: This case sheds light on the intricate interplay between nivolumab therapy, pre-existing autoimmune conditions such as Graves’ Disease, and the emergence of irAEs. This case underscores the importance of vigilant monitoring of serum sodium levels, and thyroid and pituitary function tests in patients undergoing immunotherapy. Presentation: 6/1/2024

Temporal Effect on PD-L1 Detection and Novel Insights Into Its Clinical Implications in Non-Small Cell Lung Cancer.

Several studies rely on archived tissue blocks to assess the PD-L1 scores; however, a detailed analysis of potential variations of scores between fresh and archived tissue blocks still lacks. In addition, the prognostic implications of PD-L1 in lung cancers have not yet been completely understood. Here, we aimed to investigate the temporal variation in PD-L1 scores from clinical samples and the clinical implications of PD-L1 in non-small cell lung cancer (NSCLC). NSCLC cases from January 2005 to June 2023 were considered for this study, and PD-L1 scores in archived and fresh tissue blocks were analyzed. Association of PD-L1 with various driver mutations was explored, and implications of PD-L1 in progression-free survival (PFS) and overall survival (OS) were analyzed. Our study revealed a significant disparity in PD-L1 scores between archived and fresh tissue blocks, and a temporal variation in scores within 6 months of tissue acquisition. Advanced-stage primary tumors, metastatic lymph nodes, and visceral pleural invasion revealed higher PD-L1 expression as presented by tumor proportion score (TPS). Notably, in fully resected stage I/II NSCLC cases, OS was better in the high PD-L1 (≥ 50% TPS) cohort with driver mutations compared to cases without driver mutations (hazard ratio-0.5129, 95% confidence interval 0.2058-1.084, p = 0.0779). In contrast, high PD-L1 was associated with worse OS compared to no PD-L1 (< 1% TPS) (hazard ratio-2.431, 95% confidence interval 1.144-6.656, p = 0.0242) in the cohort without driver mutations. Furthermore, the presence of a KRAS mutation favored the outcome of anti-PD-L1/PD1 immunotherapy in advanced NSCLC. PD-L1 detection from tissue blocks was found to vary temporally, urging for a prioritized consideration for patients with marginal scores when archived blocks are employed for its detection. Prognostic roles of PD-L1 were associated with driver mutations, and KRAS mutations favored the outcome of anti-PD-L1/PD1 therapy in advanced NSCLC.

Ultrasound-mediated PLGA-PEI Nanobubbles Carrying STAT6 SiRNA Enhances NSCLC Treatment via Repolarizing Tumor-associated Macrophages from M2 to M1 Phenotypes.

Tumor-associated macrophages (TAMs) are crucial for non-small cell lung cancer (NSCLC) development. In this study, polylactic acid-co-glycolic acid (PLGA)-polyethylenimine (PEI) nanobubbles (NBs) carrying STAT6 siRNA were prepared and combined with ultrasound-mediated nanobubbles destruction (UMND) to silence the STAT6 gene, ultimately repolarizing TAMs from the M2 to the M1 phenotype, treating NSCLC in vitro. PLGA-PEI NBs-siRNA were prepared and characterised, and their respective ultrasound imaging, biological stabilities and cytotoxicities were detected. Transfection efficiency was evaluated by fluorescence microscopy and flow cytometry. Repolarization of THP-1-derived M2-like macrophages was determined by qPCR and flow cytometry. NSCLC cells (A549) were co-cultured with transfected M2-like macrophages or their associated conditioned medium (CM). Western blotting was used to detect STAT6 gene silencing in M2-like macrophages and markers of epithelial and mesenchymal in A549 cells. The proliferation of A549 cells was detected using CCK-8 and cell colony formation assays. Transwell assays were used to detect the migration and invasion of A549 cells. PLGA-PEI NBs-siRNA had an average size of 223.13 ± 0.92 nm and a zeta potential of about -5.59 ± 0.97 mV. PLGA-PEI NBs showed excellent ultrasonic imaging capability in addition to biological stability to protect siRNA from degradation. UMND enhanced PLGA-PEI NBs-STAT6 siRNA transfection in M2-like macrophages, which made M2-like macrophages repolarize to M1-like macrophages and prevented proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in A549 cells. UMND enhanced PLGA-PEI NBs-STAT6 siRNA to repolarize TAMs from the M2 to the M1 phenotype, thus treating NSCLC. These findings provide a promising therapeutic approach for enhancing NSCLC immunotherapy.

Evidence for the evolving role of neoadjuvant and perioperative immunotherapy in resectable non-small cell lung cancer

The treatment of early-stage non-small cell lung cancer (NSCLC) is becoming increasingly complex. Standard of care management for the past decade has been adjuvant chemotherapy following curative intent resection regardless of nodal status or tumour profile. With the increased incorporation of immunotherapy in NSCLC, especially in the locally advanced, unresectable, or metastatic settings, multiple studies have sought to assess its utility in early-stage disease. While there are suboptimal responses to neoadjuvant chemotherapy alone, there is a strong rationale for the use of neoadjuvant immunotherapy in tumour downstaging, based upon the concept of enhanced T cell priming at the time of a high tumour antigen burden, and demonstrated clinically in other solid tumours, such as melanoma. In the NSCLC cancer setting, currently over 20 combinations of chemoimmunotherapy in the neoadjuvant and perioperative setting have been studied with results variable. Multiple large phase III studies have demonstrated that neoadjuvant chemoimmunotherapy combinations result in significant advances in pathological response, disease free and overall survival which has led to practice change across the world. Currently, combination immunotherapy regimens with novel agents targeting alternate immunomodulatory pathways are now being investigated. Given this, the landscape of treatment in resectable early-stage NSCLC has become increasingly complex. This review outlines the literature of neoadjuvant and perioperative immunotherapy and discusses its potential benefits and complexities and ongoing considerations into future research.

Review of immunotherapy in non-small cell lung cancer: mechanisms, clinical applications, and future prospects

Non-small cell lung cancer (NSCLC) ranks among the top contributors to cancer-related mortality globally. Recently, immunotherapy, particularly immune checkpoint inhibitors, has achieved groundbreaking progress in the treatment of NSCLC, significantly improving patient outcomes. This review explored the mechanisms of immunotherapy in NSCLC, with a focus on the roles of the PD-1/PD-L1 and CTLA-4 pathways. The discussion then shifted toward the currently approved and investigational immunotherapy drugs, including Nivolumab, Pembrolizumab, and Atezolizumab. Subsection sections review the recent progress of research on novel immunotherapeutic agents and biomarkers and discuss the side effects of immunotherapy. Finally, we provide an outlook on the prospects of NSCLC immunotherapy, exploring how precision medicine and personalized treatment strategies can further enhance therapeutic efficacy. In conclusion, immunotherapy for NSCLC has made significant advancements in both mechanistic research and clinical application.

LAMTOR1 decreased exosomal PD-L1 to enhance immunotherapy efficacy in non-small cell lung cancer

Great progress has been made in utilizing immune checkpoint blockade (ICB) for the treatment of non-small-cell lung cancer (NSCLC). Therapies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, expressed on tumor cells, have demonstrated potential in improving patient survival rates. An unresolved issue involves immune suppression induced by exosomal PD-L1 within the tumor microenvironment (TME), particularly regarding CD8+ T cells. Our study unveiled the crucial involvement of LAMTOR1 in suppressing the exosomes of PD-L1 and promoting CD8+ T cell infiltration in NSCLC. Through its interaction with HRS, LAMTOR1 facilitates PD-L1 lysosomal degradation, thereby reducing exosomal PD-L1 release. Notably, the ability of LAMTOR1 to promote PD-L1 lysosomal degradation relies on a specific ubiquitination site and an HRS binding sequence. The findings suggest that employing LAMTOR1 to construct peptides could serve as a promising strategy for bolstering the efficacy of immunotherapy in NSCLC. The discovery and comprehension of how LAMTOR1 inhibits the release of exosomal PD-L1 offer insights into potential therapeutic strategies for improving immunotherapy. It is imperative to conduct further research and clinical trials to investigate the feasibility and efficacy of targeting LAMTOR1 in NSCLC treatment.

The Geriatric Nutritional Risk Index as a prognostic factor in patients treated with immune checkpoint inhibitors with non-small-cell lung cancer.

Globally, non-small cell lung cancer (NSCLC) is a leading factor in cancer-related mortality. Additionally, the Geriatric Nutritional Risk Index (GNRI) has been assessed as a predictive and prognostic indicator in various types of carcinomas. Our study aims to assess the prognostic importance of GNRI computed at diagnosis in NSCLC patients receiving immune checkpoint inhibitors (ICIs). The study evaluated 148 patients who underwent immunotherapy for NSCLC from January 1, 2018, through December 31, 2021, retrospectively. Patients combined with other malignant tumors or severe comorbidities were excluded from the study. The receiver operating characteristic (ROC) curve was employed in regulating the ideal cutoff worth of GNRI. Survival outcomes were evaluated through Kaplan-Meier analysis. Following this, both univariate and multivariate analyses were conducted utilizing Cox regression analysis to identify any potential factors that may influence the survival outcomes. The cutoff point for GNRI was 108.15 [area under the curve (AUC) =0.575, P=0.048]. Further analysis using the Kaplan-Meier method demonstrated that individuals in the high GNRI group had significantly longer progression-free survival (PFS) and overall survival (OS) compared to those in the low GNRI group (P=0.02, P=0.01). The further stratified study showed that GNRI had greater predictive value in tumor node metastasis (TNM) stage II-III and elderly (age ≥65 years) NSCLC patients undergoing ICI therapy. The multivariate Cox regression analysis indicated that GNRI [hazard ratio (HR): 0.536, P=0.03], obesity (HR: 16.283, P<0.001), and surgical history (HR: 0.305, P<0.001) were associated with poorer survival rates. Among patients undergoing ICI therapy for NSCLC, GNRI is an effective independent prognostic indicator, and a high GNRI at diagnosis is substantially related with longer PFS and OS. The incorporation of GNRI in pre-treatment evaluations within clinical settings is beneficial.

Thoracic sarcopenia was a poor prognostic predictor in patients receiving immunotherapy retain-->for advanced non-small-cell retain-->lung cancer

Sarcopenia, as measured at the level of the third lumbar (L3) has been shown to predict the survival of cancer patients. However, many patients with advanced non-small cell lung cancer (NSCLC) do not undergo routine abdominal imaging. The objective of this study was to investigate the association of thoracic sarcopenia with survival outcomes among patients who underwent immunotherapy for NSCLC. In this retrospective study, patients who initiated immunotherapy for advanced NSCLC from 2019 to 2022 were enrolled. and detailed patient data were collected. Cross sectional skeletal muscle area was calculated at the fifth thoracic vertebra (T5) on pretreatment chest computed tomography (CT) scan. Gender-specific lowest quartile values was used to define sarcopenia. The risk factors were analyzed using Cox analyses. The log-rank test and the random survival forest (RSF) were used to compare progression free survival (PFS). The model's performance was assessed using calibration curve and the receiver operating characteristic curve (ROC). A total of 242 patients was included (discovery cohort n=194, validation cohort n=48). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p<0.001) than patients without sarcopenia. Univariate cox regression revealed that sarcopenia, lung cancer stage, body mass index, smoking status, and neutrophil-to-lymphocyte ratio were predictors of poor PFS. A RSF model was constructed based on the aforementioned parameters, to evaluate the model's efficacy, the ROC curve was utilized. with an area under the curve for predicting 6-month PFS of 0.68 and for 12-month PFS of 0.69. The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort. Sarcopenia at T5 is independent prognostic factors in patients who received immunotherapy for advanced NSCLC.

Preliminary analysis of PD-1 inhibitors combined with chemotherapy as neoadjuvant therapy for local advanced non-small cell lung cancer (NSCLC).

200 Background: The benefits of neoadjuvant immunotherapy and chemotherapy for resectable NSCLC suggest that this combined treatment may provide more surgical opportunities and survival benefits for potentially resectable locally advanced NSCLC. Methods: We retrospectively collected data from 28 patients with stage III EGFR/ALK/ROS wild-type NSCLC. Eligible patients received 2-8 cycles of neoadjuvant chemoimmunotherapy (squamous carcinoma: PD-1 inhibitor combined with albumin-bound paclitaxel and cisplatin/carboplatin; adenocarcinoma: PD-1 inhibitor combined with pemetrexed and carboplatin), followed by re-evaluation for surgery. Afterwards, patients underwent surgery after downstaging, with some receiving adjuvant immunotherapy maintenance for one year. Primary endpoints included major pathological response (MPR), pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Results: All 28 patients were male, with 7 (25%) in stage IIIA, 10 (35.7%) in IIIB, 4 (14.3%) in IIIC, 2 (7.14%) in IVA, and 2 (7.14%) in IVB. There were 22 cases of squamous cell carcinoma, 4 of adenocarcinoma, 1 of large cell lung cancer, and 1 of lymphoepithelioma-like carcinoma. 23 patients (82.1%) completed neoadjuvant treatment and underwent resection, achieving 100% R0 resection rate (23/23); 5 patients did not undergo surgery, 3 of whom received combined radiochemotherapy due to disease progression, 1 delayed surgery due to immunotherapy associated myocardial damage, and 1 died from massive hemoptysis and hemorrhagic shock. The objective response rate (ORR) was 60.7%, 95%CI [40.6-78.5%] and the disease control rate (DCR) was 85.7%, 95%CI [67.3-96.0%]. Among the 23 patients who underwent surgery, the pCR was 60.9%, 95%CI [38.5-80.3%], MPR was 4.3%, 95%CI [0.1-21.9%], clinical downstaging rate was 50%, 95%CI [30.6-69.4%] and pathological downstaging rate was 86.9%, 95%CI [66.4-97.2%]. 17 patients (77.3%) underwent lobectomy, and 5 (22.7%) underwent bilobectomy with a median blood loss of 100 ml, IQR [55.0-100]. There were no surgery-related deaths. Postoperatively, one patient developed chylothorax, one had a lung infection, and the two improved after conservative treatment. 11 patients (47.8%) received post-surgery immunotherapy maintenance, and 2 of them (8.7%) developed immune-related pneumonia. As of April 7, 2024, the median follow-up time was 21.5 months (95%CI: 17-34 Mo), At 12 months。 PFS rate was 82.1% (95%CI: 69.1-97.6%); OS rate was 96.3% (95%CI: 89.4-100%). Conclusions: Neoadjuvant immunotherapy combined with surgery for unresectable locally advanced NSCLC may benefit patients and significantly extend survival.

Ginsenoside Re inhibits non-small cell lung cancer progression by suppressing macrophage M2 polarization induced by AMPKα1/STING positive feedback loop.

Tumor-associated macrophages (TAMs) in non-small cell lung cancer (NSCLC) promote tumor cell metastasis by interacting with cancer cells. Ginsenoside Re is capable of modulating the host immune system and exerts anticancer effects through multiple pathways. Both AMPK and STING are involved in the regulation of MΦ polarization, thereby affecting tumor progression. However, whether there is a regulatory relationship between them and its effect on MΦ polarization and tumor progression is unclear. The aim of this study was to provide mechanistic evidence that ginsenoside Re modulates MΦ phenotype through inhibition of the AMPKα1/STING positive feedback loop and thus exerts an antimetastatic effect in NSCLC immunotherapy. Cell culture models and conditioned media (CM) systems were constructed, and the treated MΦ were analyzed by database analysis, RT-PCR, Western blotting, flow cytometry, and immunofluorescence to determine the regulatory relationship between AMPK and STING and the effects of ginsenoside Re on MΦ polarization and tumor cells migration. The effects of ginsenoside Re (10, 20 mg/kg/day) on TAMs phenotype as well as tumor progression in mice were assessed by HE staining, immunohistochemical staining, and Western blotting. In this study, AMPKα1/STING positive feedback loop in NSCLC TAMs induced M2 type polarization, which in turn promoted NSCLC cell migration. In addition, ginsenoside Re was discovered to inhibit M2-like MΦ polarization, thereby inhibiting NSCLC cell migration. Mechanistically, Re was able to inhibit the formation of the AMPKα1/STING positive feedback loop, thereby inhibiting its induction of M2-like MΦ and consequently inhibiting the epithelial-mesenchymal transition (EMT) process of NSCLC cells. Furthermore, in mouse models, Re was found to suppress LLC tumor growth and colonization by inhibiting M2-type polarization of TAMs. Our finding indicates that ginsenoside Re can effectively modulate MΦ polarization and thus play an important role in antimetastatic immunotherapy of NSCLC.

The current therapeutic cancer vaccines landscape in non-small cell lung cancer.

Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue.

Association between thymus density loss and efficacy in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

Although the thymus undergoes degeneration with the advancement of age, recent studies have continuously revealed that the thymus possesses the potential for regeneration and may reverse this aging trend. Furthermore, an increasing number of studies indicate an association between thymus function and immunotherapy. Considering that lung cancer patients typically undergo chest computed tomography (CT) scans during treatment, this provides convenient conditions for us to observe thymic remodeling through imaging data. Therefore, exploring the changes in the thymus on CT images is of great significance for understanding its relationship with the efficacy of immunotherapy in non-small cell lung cancer (NSCLC) patients. This study investigated the CT imaging characteristics of thymic density changes in patients with advanced NSCLC after immunotherapy. The primary objective was to determine whether changes in thymic density are predictors of response to immunotherapy in patients with NSCLC. A total of 412 patients with advanced NSCLC who underwent immunotherapy were included. Thymic density measurements were taken initially and after immunotherapy, with the annualized change calculated. Comprehensive analysis, including disease progression, survival, and subgroup assessments, was conducted. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). The annual change in density of the thymic region ranged from -108 to 108 HU after the initiation of ICIs. Patients were categorized into "loss" or "non-loss" groups (210 vs. 202) based on thymic density changes. Analysis of short-term progression of solid tumors revealed no statistically significant differences in ORR (P=0.55) and DCR (P=0.67) between the two groups. Throughout the entire follow-up period, 41 patients (19.5%) in the "loss" group and 64 patients (31.7%) in the "non-loss" group died. Thymic density reduction was not associated with PFS (P=0.08), but it was positively associated with increased OS (P=0.003). The results were consistent across subgroups. Thymic density changes were observed in nearly all NSCLC patients undergoing immunotherapy, with decreased density associated with longer OS. These findings suggest a potential association between thymic density changes and immune efficacy in NSCLC immunotherapy.

Progress of IL-21 and Tfh Mediated Immunotherapy in Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is a prevalent and aggressive global malignancy. Conventional surgical treatments, radiotherapy, chemotherapy, and targeted therapies often fall short in halting disease progression due to inherent limitations, resulting in suboptimal prognosis. Despite the advent of immunotherapy drugs offering new hope for NSCLC treatment, current efficacy remains insufficient to meet all patient needs. Therefore, actively exploring novel immunotherapeutic approaches to further reduce mortality rates in NSCLC patients has become a crucial focus of NSCLC research. This article aims to systematically review the anti-tumor effects of interleukin-21 and follicular helper T cells in NSCLC immunotherapy by summarizing and analyzing relevant literatures from both domestic and international sources, as well as exploring the potential for enhancing NSCLC treatment prospects through immune checkpoint regulation via immunotherapeutic means. .

Prognostic value of immunotherapy in advanced NSCLC based on baseline and dynamic changes in HALP

Immune checkpoint inhibitors (ICIs) enhance the tumor-killing ability of T-cells in non-small cell lung cancer (NSCLC), improving overall survival (OS) and revolutionizing treatment for advanced stages. However, challenges remain, such as low response rates and the lack of effective markers for selecting candidates. This study evaluated the impact of hemoglobin, albumin, and platelet (HALP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on the efficacy of immunotherapy and survival outcomes in advanced NSCLC. Additionally, it aimed to develop a nomogram based on these parameters. Clinical and hematological data from NSCLC patients who received immunotherapy were analyzed. Efficacy was assessed using the immune Response Evaluation Criteria in Solid Tumors (iRECIST), and progression-free survival (PFS) and OS were evaluated. Prediction models incorporated baseline and post-treatment HALP, NLR, and PLR values. The 203 patients had a median follow-up of 16 months, a median PFS (mPFS) of seven months (6.0–8.0), while the median OS (mOS) was not reached (24.0–not available). Pretreatment PLR (PLR0) was associated with a higher disease control rate (DCR) (odds ratio [OR] = 0.258), while initial immunotherapy and NLR after four treatment cycles (NLR4C) significantly improved the objective response rate (ORR). Cox regression analysis showed that pretreatment HALP (HALP0), HALP after four cycles of treatment (HALP4C), and pretreatment NLR (NLR0) significantly impacted PFS. Additionally, HALP0, NLR0, and PLR after four treatment cycles (PLR4C) were associated with OS. The C-indices for PFS and OS were 0.823 and 0.878, respectively, indicating good predictive accuracy. HALP, NLR, and PLR at various time points effectively predicted immunotherapy response in advanced NSCLC patients, with low HALP combined with high NLR and PLR indicating a poor prognosis. These findings could serve as the basis for stratified randomized controlled trials (RCTs) in the future.

Efficacy of immunotherapy in RET fusion-positive NSCLC: A meta-analysis

BackgroundThe Rearranged during Transfection (RET) gene represents a rare driver mutation in non-small cell lung cancer (NSCLC) occurring in only 1 %–2 % of cases, with implications in targeted carcinogenesis. Despite the significant efficacy demonstrated by immunotherapy in advanced NSCLC with wild-type driver genes, its validation in RET fusion-positive patients is yet to be established. ObjectivesThis meta-analysis aims to systematically evaluate the effectiveness of immunotherapy in patients with RET fusion-positive NSCLC. Data sourcesand Methods: PubMed and Web of Science databases were systematically searched for relevant studies. Outcomes including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were extracted for further analysis. ResultsTen real-world evidence (RWE) studies involving 7145 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 24.0 % and 61.0 %, respectively. Regarding survival analysis, the pooled median PFS and median OS were 4.17 months [95 % confidence interval (CI): 3.40–5.02) and 17.22 months (95 % CI: 11.58–23.91)], respectively. Subgroup analyses showed that immunotherapies plus chemotherapy were superior to single-immunotherapy in terms of ORR, DCR, and median PFS, which were 43 % (95 % CI: 31%–55 %) vs. 17 % (95 % CI: 11%–25 %), 74 % (95 % CI: 60%–84 %) vs. 45 % (95 % CI: 31%–59 %) and 6.69 months (95 % CI: 4.91–8.93) vs. 2.96 months (95 % CI: 2.25–3.78), respectively. ConclusionsTo date, RET fusions appear to be associated with poor response to immunotherapy in NSCLC patients, and immunotherapy combined with chemotherapy seems to offer greater clinical benefits than mono-immunotherapy.

Impact of antibiotics, corticosteroids, and microbiota on immunotherapy efficacy in patients with non-small cell lung cancer

Lung cancer is a leading cause of morbidity and mortality globally, with its high mortality rate attributed mainly to non-small cell lung cancer (NSCLC). Although immunotherapy with immune checkpoint inhibitors (ICI) has revolutionized its treatment, patient response is highly variable and lacking predictive markers. We conducted a prospective study on 55 patients with NSCLC undergoing ICI therapy to identify predictive markers of both response and immune-related adverse events (IrAEs) in the airway microbiota. We also analyzed the clinical evolution and overall survival (OS) with respect to treatments that affect the integrity of the microbiota, such as antibiotics and corticosteroids. Our results demonstrated that respiratory microbiota differ significantly in ICI responders: they have higher alpha diversity values and lower abundance of the Firmicutes phylum and the Streptococcus genus. Employing a logistic regression model, the abundance of Gemella was the major predictor of non-ICI response, whereas Lachnoanaerobaculum was the best predictor of a positive response to ICI. The most relevant results were that antibiotic consumption is linked to a lower ICI response, and the use of corticosteroids correlated with poorer overall survival. Whereas previous studies have focused on gut microbiota, our findings highlight the importance of the respiratory microbiota in predicting the treatment response. Future research should explore microbiota modulation strategies to enhance immunotherapy outcomes. Understanding the impact of antibiotics, corticosteroids, and microbiota on NSCLC immunotherapy will help personalize treatment and improve patient outcomes.

Early monitoring of plasma KRAS G12C with digital PCR predicts antitumor response to immunotherapy or sotorasib in advanced NSCLC: A brief report

BackgroundThe frontline management of non-oncogene addicted non-small cell lung cancer (NSCLC) involves immune-checkpoint inhibitors (ICI) alone or combined with chemotherapy (CT-ICI). The dynamic landscape of KRAS-positive NSCLC presents a spectrum of treatment options, including ICIs, targeted therapy and combination strategies currently under investigation. MethodsWe conducted a prospective project to detect circulating tumor DNA (ctDNA) in patients with KRAS G12C, advanced NSCLC. We included patients undergoing upfront ICIs or subsequent line sotorasib. We planned three-time points: baseline (T0), after 3 months of treatment (T1) and at disease progression (T2). Results24 consecutive patients have been included. The most frequent baseline characteristics were: nonsquamous histology (95.8%), male gender (62.5%), ECOG PS 0–1 (79.2%), <3 metastatic sites (13/24, 54.2%). 18 patients (75%) received ICI-based strategies and 6 patients (25%) sotorasib. Patients with liver metastases (p ​= ​0.01) and those with >3 metastatic sites (p ​= ​0.002) exhibited significantly elevated ctDNA. Median overall survival (OS) was 7.5 months, progression-free survival (PFS) was 4.0 months and the objective response rate (ORR) was 33.3%. Higher AF correlated with an increased risk of death (HR 1.04, p ​= ​0.03), though not progression. The mOS was 7.5 months (95% CI, 1.91-NR) in high-AF group and 11.3 months (95% CI, 6.6-NR) in low-AF group (p ​= ​0.38). Notably, a reduction in plasma DNA levels was significantly associated with objective response (p ​= ​0.01). Two patients received a T2 dosage showing increased ctDNA levels after a previous reduction associated with response. ConclusionEarly monitoring with ctDNA may offer potential benefits in the evolving scenario of KRAS G12C NSCLC treatment.