Chemotherapy In Non-small Cell Lung Cancer Research Articles

Efficacy of radiolabelled PD-L1-targeted nanobody in predicting and evaluating the combined immunotherapy and chemotherapy for resectable non-small cell lung cancer.

This study aimed to assess the predictive and evaluative value of PD-L1 targeted 68Ga-THP-APN09 PET/CT in the neoadjuvant immunotherapy combined with chemotherapy for resectable non-small cell lung cancer (NSCLC), and to explore its potential in indicating immunotherapy-related adverse effects (irAEs). Fifty patients with resectable NSCLC enrolled in this prospective study underwent baseline 68Ga-THP-APN09 PET/CT and 18F-FDG PET/CT, with follow-up 18F-FDG PET/CT conducted, additionally, 36 patients received follow-up 68Ga-THP-APN09 PET/CT. Surgery was performed following 2-4 cycles of toripalimab combined with chemotherapy if R0 resection was feasible. The major pathologic response (MPR) state of the post-operative specimen and the adverse effects following combined therapy were documented. The correlation between PD-L1 expression and baseline 68Ga-THP-APN09 PET/CT uptake was determined. The predictive and evaluative efficacies of baseline and follow-up 68Ga-THP-APN09 PET/CT, along with 18F-FDG PET/CT, in determining MPR, were compared. The SUVmax values of baseline 68Ga-THP-APN09 PET/CT were significantly higher in patients exhibiting high-positive PD-L1 expression compared to those with low-positive and negative expression (P = 0.001). And the SUVmax values of baseline 68Ga-THP-APN09 PET/CT in the response group, as determined by 18F-FDG PET/CT evaluation, were significantly higher than those in the non-response group (3.4 vs. 2.4, P < 0.001). Totally, 41 patients underwent surgery, of which 27 achieved MPR, while 14 did not. The SUVmax in baseline 68Ga-THP-APN09 PET/CT demonstrated statistical significance between the MPR and non-MPR groups, with area under the ROC curve (AUC) of 0.88 (95%CI: 0.77-0.99) in identifying MPR. However, the SUVmax in baseline 18F-FDG PET/CT failed to demonstrated significant predictive power, with AUC values of 0.68 (95%CI: 0.50-0.86, P = 0.076). While the SUVmax in follow-up 68Ga-THP-APN09 and 18F-FDG PET/CT, along with their change rate (ΔSUVmax%), demonstrated good predictive efficacy in identifying MPR, with AUC values of 0.81 (0.64-0.98), 0.91 (0.82-1.00), 0.93 (0.84-1.00), and 0.96 (0.89-1.00), respectively. Furthermore, the follow-up 68Ga-THP-APN09 PET/CT could remarkedly indicate the potential for thyroiditis. Baseline 68Ga-THP-APN09 PET/CT alone could predict efficacy and assist in patient screening for immunotherapy combined chemotherapy in resectable NSCLC, and the follow-up 68Ga-THP-APN09 PET/CT and their change rates could aid in therapy evaluation. Additionally, follow-up 68Ga-THP-APN09 PET/CT could be utilized to monitor the immunotherapy-related thyroiditis during the therapy. NCT05156515, registered 8 December 2021, https://register. gov/prs/app/action/SelectProtocol?sid=S000BMSI%26;selectaction=Edit%26;uid=U000503E%26;ts=2%26;cx=zeghuw .

Self-assembly of multi-arm star PEG containing TXA9 into nanoparticle for the efficient chemotherapy of NSCLC.

TXA9, a cardiac glycoside isolated from the root of Streptocaulon juventas (Lour.) Merr., with better therapeutic effect in vitro on non-small cell lung cancer (NSCLC) than cisplatin and has no toxic side effects on the body. However, poor water solubility and rapid metabolism limited its clinical application. Multi-arm star PEG have many advantages over linear PEG, such as high drug loading due to more terminals and better anti-hemodilution ability, which have become popular carriers for drug delivery. In this study, to improve the efficacy of TXA9, 6/8armPEGn-Glycine Carbamate (Gly) (n = 10, 20, and 40kDa) were used as carriers to prepare star PEG-TXA9 conjugates. The particle size and zeta potential of six prodrug NPs for effective tumor targeting, with suitable drug loading, and good water solubility. Compared with free TXA9, 6/8APGn-T NPs had more significant anti-tumor effects in vitro. Since the multi-arm star PEG formed an "umbrella" structure on the surface of NPs, the 8APG40k-T NPs with the best pharmacokinetic properties increased half-life of TXA9 about 60 times in vivo. In addition, the arm numbers and molecular weight of multi-arm star PEGs significantly influenced the in vivo destiny of prodrugs. In vivo experiments showed that the same dose of 8APG40k-T NPs increased the tumor inhibition rate about 3.56 or 1.22 times compared with TXA9 or cisplatin, and had good biocompatibility. This study provides a simple but effective strategy to solve the challenges caused by the poor water solubility and short half-life of TXA9 for developing the TXA9 as a safe and effective drug against NSCLC.

Neoadjuvant atezolizumab + chemotherapy for resectable NSCLC: 3-year clinical update of phase II clinical trial results and translational findings.

Neoadjuvant chemoimmunotherapy has achieved overall survival (OS) benefit for patients with resectable non-small cell lung cancer (NSCLC). Here, we present outcomes after 3 years of follow-up from the first reported study of neoadjuvant atezolizumab+chemotherapy. This open-label, multicenter single-arm investigator-initiated phase II study conducted at three US hospitals tested up to four cycles of atezolizumab, carboplatin, and nab-paclitaxel prior to surgery. Major pathological response (MPR, primary endpoint) was previously reported; here, we report 3-year disease-free survival (DFS), OS, and clinical characteristics of patients developing brain metastases (BM) with integrated data from tumor genomics, gene expression, and quantitative immunofluorescent measurement of immune markers. Of 30 enrolled patients, 29 were taken to the operating room. 26 underwent R0 resection, with 17 experiencing MPR (10 pCR). With a median follow-up of 39.5 months, the median OS was 55.8 months, and the median DFS was 34.5 months. Landmark OS at 36 months was 77%. Among 14 patients with recurrent disease, 6 patients had BM. Patients whose tumors had mutations in STK11 and KEAP1 did not have a significantly higher incidence of BM. Reduced copy number of STK11 and KEAP1, both residing on chromosome 19p, was observed in ~1/3 of tumors. Reduced CN of STK11 was significantly associated with worse pathological response and incidence of BM. Consistent with recent phase III studies, 3-year OS data with neoadjuvant atezolizumab+chemotherapy was associated with prolonged PFS and OS. Establishing associations between STK11 and KEAP1 genomic alterations and key clinical outcomes in early-stage NSCLC requires further study.

Exploring acenocoumarol and silodosin as allosteric EGFR inhibitors for the treatment of non-small cell lung cancer

Background Non-small-cell lung cancer (NSCLC) is a highly morbid disease. Chemotherapy for NSCLC lacks specificity and efficacy mainly because of drug resistance. The current study aimed to explore computational tools to target allosteric epidermal growth factor receptor (EGFR) sites and screen for the top molecules in vitro and in vivo xenograft models. Methods Molecular docking, virtual screening, and molecular dynamic studies revealed that acenocoumarol and silodosin are the top two allosteric EGFR inhibitors. They were further tested for cytotoxicity, apoptosis, cell cycle, and gene expression by qPCR, western blotting, A549 cell xenograft anti-proliferative activity, and tumor regression efficacy analysis. Results Acenocoumarol and silodosin exhibited cytotoxicity in A549 and IMR-90 cells at concentrations below 50 and 80 μM, respectively. Acenocoumarol and silodosin induced S-phase and G2/M-phase arrest in A549 cells in the cell cycle analysis. Both drugs showed early apoptosis at their IC50 doses (acenocoumarol 50 μM and silodosin 25 μM). KRAS (Kirsten rat sarcoma viral oncogene homolog) and ERK2 (extracellular signal-regulated kinase 2) gene regulation in A549 cells was confirmed using qPCR. KRAS and ERK2 activities were quantified by western blot analysis. In the xenograft study, tumor size, body weight, and organ weight were significantly attenuated by the test drugs compared with the standard cisplatin. Immunoblotting and western blot results of the A549-xenograft tissue indicated downregulation of KRAS and ERK2. Furthermore, the test drugs have upregulated caspase-3 gene expression. Conclusion The drugs acenocoumarol and silodosin downregulate KRAS and ERK2 both in cell line and in Xenograft model. KRAS and ERK2 are associated with EGFR inhibition. Hence, acenocoumarol and silodosin can be further explored for repurposing studies in human trials.

Immune checkpoint inhibitors in driver mutation-positive nonsmall cell lung cancer.

Immune checkpoint inhibitors (ICIs) and targeted therapies have changed the landscape of management of nonsmall cell lung cancer (NSCLC) dramatically. Whereas ICIs in NSCLC without specific driver mutations are well established it is unclear what the place of ICIs in driver mutation-positive NSCLC is. This review summarizes the current view on the use of ICIs in driver mutation-positive NSCLC. Immune checkpoint inhibition in combination with chemotherapy (and antiangiogenesis) in recurrent driver mutation-positive NSCLC after tyrosine kinase inhibitor therapy may be effective. Currently the role of immune checkpoint inhibitors in driver mutation-positive NSCLC is limited. They can in combination be applied in second and later line settings if no specific therapy is available.

Novel FABP4+C1q+ macrophages enhance antitumor immunity and associated with response to neoadjuvant pembrolizumab and chemotherapy in NSCLC via AMPK/JAK/STAT axis

Immune checkpoint inhibitors (ICIs) immunotherapy facilitates new approaches to achieve precision cancer treatment. A growing number of patients with non-small cell lung cancer (NSCLC) have benefited from treatment with neoadjuvant ICIs combined with chemotherapy. However, the mechanisms and associations between the therapeutic efficacy of neoadjuvant pembrolizumab and chemotherapy (NAPC) and macrophage subsets are still unclear. We performed single-cell RNA sequencing (scRNA-seq) and identified a novel FABP4+C1q+ macrophage subtype, which exhibited stronger proinflammatory cytokine production and phagocytic ability. This subtype was found to be more abundant in tumor tissues and lymph nodes of major pathological response (MPR) patients compared to non-MPR patients, and was associated with a good efficacy of NAPC. Multiplex fluorescent immunohistochemical (mIHC) staining was subsequently used to verify our findings. Further mechanistic studies indicated that FABP4 and C1q regulate the expression of proinflammatory cytokines synergistically. In addition, FABP4 and C1q promote fatty acid synthesis, enhance anti-apoptosis ability and phagocytic ability of macrophage via the interaction of AMPK/JAK/STAT axis. This study provides novel insights into the underlying mechanisms and predictive biomarkers of NAPC. Our findings contribute to improving the prognosis of patients with NSCLC by potentially guiding more precise patient selection and treatment strategies.Novelty & Impact StatementsWe identified a group of macrophages (FABP4+C1q+ macrophages) related to the therapeutic efficacy of neoadjuvant chemoimmunotherapy. FABP4+C1q+ macrophages highly expressed proinflammatory cytokines-related genes and had a strong cytokine production and phagocytic ability. We believe that our study provides a novel insight into the synergistic mechanism of neoadjuvant ICI combined with chemotherapy and may lead to improved clinical outcomes in patients with NSCLC in the future.

Perioperative PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer: A meta-analysis based on randomized controlled trials.

PD-1/PD-L1 inhibitors (PI) have shown promising results in both neoadjuvant and adjuvant therapies for resectable non-small cell lung cancer (NSCLC). However, substantial evidence from large-scale studies is still lacking for their use in the perioperative setting (neoadjuvant plus adjuvant). This meta-analysis aims to evaluate the integration of perioperative PI (PPI) with neoadjuvant chemotherapy for resectable NSCLC. To identify appropriate randomized controlled trials (RCTs), we thoroughly explored six different databases. The primary endpoint was survival, while the secondary measures included pathological responses and adverse events (AEs). Six RCTs involving 2941 patients were included. The PPI group significantly improved overall survival (OS) (hazard ratio [HR]: 0.62 [0.51, 0.77]), event-free survival (EFS) (HR: 0.57 [0.51, 0.64]), pathological complete response (risk ratio [RR]: 5.81 [4.47, 7.57]), and major pathological response (RR: 2.60 [1.77, 3.82]). Benefits in EFS were seen across all subgroups. OS rates at 12-48 months and EFS rates at 6-48 months were higher in the PPI cohort. Furthermore, the advantages in OS and EFS increased with prolonged survival times. The PPI group also exhibited higher rates of surgery and R0 resections. However, the PPI group experienced more grade 3-5 AEs, serious AEs, and treatment discontinuations due to AEs. The integration of perioperative PI with neoadjuvant chemotherapy can significantly improve survival and pathological responses for resectable NSCLC. However, the increased incidence of grade 3-5 AEs must be carefully evaluated.

Exploring Genetic Variants and Platinum Chemotherapy Response in Indonesian Non-Small Cell Lung Cancer Patients: Insights from ERCC2 rs13181.

Individual responses to platinum-based treatment for Non-Small Cell Lung Cancer (NSCLC) are influenced by genetic polymorphisms, including Single Nucleotide Polymorphisms (SNPs). This study aimed to explore the role of ERCC2 in the Nucleotide Excision Repair (NER) pathway for platinum-based chemotherapy in NSCLC. While ERCC2 is widely studied, data for Southeast Asian populations are lacking. Addressing this gap could improve personalized treatment strategies for NSCLC in this demographic. This study recruited 82 NSCLC patients with wildtype mutations of EGFR at Dr. H.A. Rotinsulu Lung Hospital, Bandung, and Dharmais Cancer Hospital, Jakarta. Data were collected prospectively from whole blood samples and medical records, while the effectiveness of chemotherapy was assessed by evaluating the response using RECIST 1.1 criteria on fourth cycle of chemotherapy. The results of this study showed the presence of genotype variation among the subjects, with frequency distribution as follows: AA genotype (82.9%), AC genotype (15.9%), and CC genotype (1.2%). The analysis of the association between ERCC2 rs13181 CC + AC versus AA with RECIST 1.1 yielded an odds ratio (OR) of 1.042 (95% CI: 0.292-3.715; p=0.950). A multivariate analysis that included cancer stage and chemotherapy regimen as additional variables produced an adjusted odds ratio (aOR) of 0.970 (95% CI: 0.263-3.568; p=0.963). This study did not find statistically significant associations between ERCC2 rs13181 polymorphisms and chemotherapy responses. However, this research highlights the presence of genetic variation within the Indonesian population, with the AA genotype being the most prevalent, which may influence chemotherapy responses. The results provided preliminary data and lay the foundation for future comprehensive cohort observational investigations.

Combined Chemo- and Photothermal Therapies of Non-Small Cell Lung Cancer Using Polydopamine/Au Hollow Nanospheres Loaded with Doxorubicin.

The chemotherapeutic agent doxorubicin (DOX) is limited by its cardiotoxicity, posing challenges in its application for non-small cell lung cancer (NSCLC). This study aims to explore the efficacy of polydopamine/Au nanoparticles loaded with DOX for chemotherapy and photothermal therapy in NSCLC to achieve enhanced efficacy and reduced toxicity. Hollow polydopamine (HPDA)/Au@DOX was synthesized via polydopamine chemical binding sacrificial template method. Morphology was characterized using transmission electron microscopy, particle size and potential were determined using dynamic light scattering, and photothermal conversion efficiency was assessed using near-infrared (NIR) thermal imaging. Drug loading rate and in vitro drug release were investigated. In vitro, anti-tumor experiments were conducted using CCK-8 assay, flow cytometry, and live/dead cell staining to evaluate the cytotoxicity of HPDA/Au@DOX on A549 cells. Uptake of HPDA/Au@DOX by A549 cells was detected using the intrinsic fluorescence of DOX. The in vivo anti-metastasis and anti-tumor effects of HPDA/Au@DOX were explored in mouse lung metastasis and subcutaneous tumor models, respectively. HPDA/Au@DOX with a particle size of (164.26±3.25) nm, a drug loading rate of 36.31%, and an encapsulation efficiency of 90.78% was successfully prepared. Under 808 nm laser irradiation, HPDA/Au@DOX accelerated DOX release and enhanced uptake by A549 cells. In vitro photothermal performance assessment showed excellent photothermal conversion capability and stability of HPDA/Au@DOX under NIR laser irradiation. Both in vitro and in vivo experiments demonstrated that the photothermal-chemotherapy combination group (HPDA/Au@DOX+NIR) exhibited stronger anti-metastatic and anti-tumor activities compared to the monotherapy group (DOX). HPDA/Au@DOX nanosystem demonstrated excellent photothermal effect, inhibiting the growth and metastasis of A549 cells. This nanosystem achieves the combined effect of chemotherapy and photothermal, making it promising for NSCLC treatment.

Genomic correlates of the response to first-line PD-1 blockade plus chemotherapy in patients with advanced non-small-cell lung cancer.

Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC. We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort (n=125), a validation cohort (n=82), and a control cohort (n=80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment. These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with 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.

TFEB controls sensitivity to chemotherapy and immuno-killing in non-small cell lung cancer

BackgroundIn non-small cell lung cancer (NSCLC) the efficacy of chemo-immunotherapy is affected by the high expression of drug efflux transporters as ABCC1 and by the low expression of ABCA1, mediating the isopentenyl pyrophosphate (IPP)-dependent anti-tumor activation of Vγ9Vδ2 T-lymphocytes. In endothelial cells ABCA1 is a predicted target of the transcription factor EB (TFEB), but no data exists on the correlation between TFEB and ABC transporters involved in the chemo-immuno-resistance in NSCLC.MethodsThe impact of TFEB/ABCC1/ABCA1 expression on NSCLC patients’ survival was analyzed in the TCGA-LUAD cohort and in a retrospective cohort of our institution. Human NSCLC cells silenced for TFEB (shTFEB) were analyzed for ABC transporter expression, chemosensitivity and immuno-killing. The chemo-immuno-sensitizing effects of nanoparticles encapsulating zoledronic acid (NZ) on shTFEB tumors and on tumor immune-microenvironment were evaluated in Hu-CD34+ mice by single-cell RNA-sequencing.ResultsTFEBlowABCA1lowABCC1high and TFEBhighABCA1highABCC1low NSCLC patients had the worst and the best prognosis, respectively, in the TCGA-LUAD cohort and in a retrospective cohort of patients receiving platinum-based chemotherapy or immunotherapy as first-line treatment. By silencing shTFEB in NSCLC cells, we demonstrated that TFEB was a transcriptional inducer of ABCA1 and a repressor of ABCC1. shTFEB cells had also a decreased activity of ERK1/2/SREBP2 axis, implying reduced synthesis and efflux via ABCA1 of cholesterol and its intermediate IPP. Moreover, TFEB silencing reduced cholesterol incorporation in mitochondria: this event increased the efficiency of OXPHOS and the fueling of ABCC1 by mitochondrial ATP. Accordingly, shTFEB cells were less immuno-killed by the Vγ9Vδ2 T-lymphocytes activated by IPP and more resistant to cisplatin. NZ, which increased IPP efflux but not OXPHOS and ATP production, sensitized shTFEB immuno-xenografts, by reducing intratumor proliferation and increasing apoptosis in response to cisplatin, and by increasing the variety of anti-tumor infiltrating cells (Vγ9Vδ2 T-lymphocytes, CD8+T-lymphocytes, NK cells).ConclusionsThis work suggests that TFEB is a gatekeeper of the sensitivity to chemotherapy and immuno-killing in NSCLC, and that the TFEBlowABCA1lowABCC1high phenotype can be predictive of poor response to chemotherapy and immunotherapy. By reshaping both cancer metabolism and tumor immune-microenvironment, zoledronic acid can re-sensitize TFEBlow NSCLCs, highly resistant to chemo- and immunotherapy.

Early-Stage Non-Small Cell Lung Cancer: New Challenges with Immune Checkpoint Blockers and Targeted Therapies.

The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC.

Cancer cell-derived exosome based dual-targeted drug delivery system for non-small cell lung cancer therapy

Lung cancer is among most prevalent cancers in the world, in which non-small cell lung cancer (NSCLC) accounts for more than 85 % of all subtypes of lung cancers. NSCLC is often diagnosed at an advanced stage with a high mortality rate. Despite the demonstrated efficacy of chemotherapy in the treatment of NSCLC, the main drawback of current therapy is the lack of an effective drug-targeted delivery system, which may result in undesirable side effects during the clinical treatment. In this study, we construct a "dual-targeting" anti-cancer drug delivery platform by combining superparamagnetic iron oxide nanoparticles (SPIONs) with exosomes derived from NSCLC cells. We successfully promoted the targeted delivery of anti-drug doxorubicin (DOX) at the cellular levels by combining the homing targeted ability of exosomes with the magnetic targeted ability of SPIONs. Moreover, non-small cell lung cancer cell (NCI-h1299) tumor models were established. It was found that exosome-SPIONs (Exo-SPIONs) loaded with DOX exhibited optimal tumor tissue delivery and tumor suppression in the presence of an external magnetic field, and reduced the toxicity of the DOX to normal tissues. The constructed "dual-targeting" anti-cancer drug delivery platform holds promise for targeted chemotherapy for NSCLC.

Preliminary experience of surgery after neoadjuvant immunotherapy combined with chemotherapy for stage-IIIB non-small cell lung cancer.

Previously, stage-IIIB non-small cell lung cancer (NSCLC) has been considered inoperable. In recent years, neoadjuvant immunotherapy has shown encouraging efficacy in the treatment of advanced stage NSCLC in several trials. However, the effectiveness and safety of neoadjuvant immunotherapy in treating stage-IIIB NSCLC are still unknown. Therefore, we conducted this retrospective study to examine the outcomes of surgery after neoadjuvant immunotherapy combined with chemotherapy for stage-IIIB NSCLC. Thirty patients with stage-IIIB NSCLC who were treated at the Department of Thoracic Surgery of Renji Hospital from January 2019 to September 2021 were analyzed retrospectively. Neoadjuvant immunotherapy combined with chemotherapy was administered prior to surgery. The curative effect was evaluated by imaging and pathological examinations. The objective response rate (ORR) and disease control rate (DCR) of the patients after neoadjuvant therapy evaluated by imaging studies were 70% and 86.7%, respectively. Of the 30 patients, 19 (63%) underwent surgical resection, in which all achieved a complete R0 resection. The median operative time was 168 minutes (range, 75-295 minutes), and the average intraoperative blood loss was 215.3±258.4 mL. The median postoperative hospital stay was 8 days (range, 4-59 days). The major pathological response (MPR) rate was 73.7% (14/19), and the pathological complete response rate was 47.4% (9/19); 2/30 patients (6.7%) had postoperative complications, including two who developed bronchopleural fistulas and one mortality, from a postoperative pulmonary infection. The treatment-related adverse reactions were mainly grades 1-2. Only two patients had grade 3 anemia, and no grade 4 adverse reactions were observed. Neoadjuvant immunotherapy and chemotherapy combined with surgery in patients with stage-IIIB NSCLC is safe and feasible. The patient outcomes and optimal number of neoadjuvant treatment cycles need to be explored and studied further.

Traditional Chinese medicine combined with chemotherapy in the treatment of advanced non-small cell lung cancer: key drug screening and mechanism analysis.

In the course of clinical treatment for anti-tumor, the combination of traditional Chinese medicine (TCM) and other treatment schemes can reduce toxicity and increase efficiency. The purpose of this paper is to find out the key TCM and effective components for the treatment of non-small cell lung cancer (NSCLC) and analyze its therapeutic mechanism by analyzing the prescription of TCM combined with chemotherapy for NSCLC. Firstly, the prescriptions of TCM in the randomized controlled trials combined with chemotherapy for NSCLC were collected, and the core TCM was screened by frequency statistics, association rule analysis, and cluster analysis. Then, the intersection targets of the potential effects of NSCLC and core Chinese medicine were collected, and PPI analysis and enrichment analysis were performed on the intersection targets to screen the core targets, components, and pathways. The core components were verified by molecular docking and cell experiments. In this study, 269 prescriptions were collected, among which the frequency of medication for Astragalus membranaceus (HQ, in Chinese), Wolfiporia cocos (FL, in Chinese), and Atractylodes macrocephala (BZ, in Chinese) was over 100. Association rule analysis showed that they were highly correlated and clustered into the same category in cluster analysis. Their core components were quercetin, kaempferol, and isorhamnetin. The molecular docking results of the core components with the core targets AKT1 and EGFR obtained by PPI network analysis showed that they could bind stably. KEGG analysis screened 110 pathways including PI3K-Akt; the results of CCK-8 showed that quercetin, kaempferol, and isorhamnetin could effectively inhibit the proliferation of A549 cells, and isorhamnetin had the best inhibitory effect. Isorhamnetin can inhibit the migration and invasion of A549 cells, induce apoptosis and G1 phase arrest, and decrease the expression of P-PI3K and P-AKT in A549 cells. In a word, the key TCM for the treatment of NSCLC includes HQ, FL, and BZ. and its key components quercetin, kaempferol, and isorhamnetin have potential therapeutic effects on NSCLC according to the research results.

Methionine Restriction Reduces Lung Cancer Progression and Increases Chemotherapy Response.

Targeting tumor metabolism through dietary interventions is an area of growing interest, and may help to improve the significant mortality of aggressive cancers, including non-small cell lung cancer (NSCLC). Here we show that the restriction of methionine in the aggressive KRAS /Lkb1- mutant NSCLC autochthonous mouse model drives decreased tumor progression and increased carboplatin treatment efficacy. Importantly, methionine restriction during early stages of tumorigenesis prevents the lineage switching known to occur in the model, and alters the tumor immune microenvironment (TIME) to have fewer tumor-infiltrating neutrophils. Mechanistically, mutations in LKB1 are linked to anti-oxidant production through changes to cystathionine-β-synthase (CBS) expression. Human cell lines with rescued LKB1 show increased CBS levels and resistance to carboplatin, which can be partially rescued by methionine restriction. Furthermore, LKB1 rescued cells, but not mutant cells, show less G2- M arrest and apoptosis in high methionine conditions. Knock-down of CBS sensitized both LKB1 mutant and non-mutated lines to carboplatin, again rescuing the carboplatin resistance of the LKB1 rescued lines. Given that immunotherapy is commonly combined with chemotherapy for NSCLC, we next wanted to understand if T cells are impaired by MR. Therefore, we examined the ability of T cells from MR and control tumor bearing mice to proliferate in culture and found that T cells from MR treated mice had no defects in proliferation, even though we continued the MR conditions ex vivo . We also identified that CBS is most highly correlated with smoking, adenocarcinomas with alveolar and bronchiolar features, and adenosquamous cell carcinomas, implicating its roles in oxidative stress response and lineage fate in human tumors. Taken together, we have shown the importance of MR as a dietary intervention to slow tumor growth and improve treatment outcomes for NSCLC.

Integrative Approaches in Non-Small Cell Lung Cancer Management: The Role of Radiotherapy.

Treatment guidelines for non-small cell lung cancer (NSCLC) vary by several factors including pathological stage, patient candidacy, and goal of treatment. With many therapeutics and even more combinations available in the NSCLC clinician's toolkit, a multitude of questions remain unanswered vis-a-vis treatment optimization. While some studies have begun exploring the interplay among the many pillars of NSCLC treatment-surgical resection, radiotherapy, chemotherapy, and immunotherapy-the vast number of combinations and permutations of different therapy modalities in addition to the modulation of each constituent therapy leaves much to be desired in a field that is otherwise rapidly evolving. Given NSCLC's high incidence and lethality, the experimentation of synergistic benefits that combinatorial treatment may confer presents a ripe target for advancement and increased understanding without the cost and burden of novel drug development. This review introduces, synthesizes, and compares prominent NSCLC therapies, placing emphasis on the interplay among types of therapies and the synergistic benefits some combinatorial therapies have demonstrated over the past several years.

STAT3-specific nanocarrier for shRNA/drug dual delivery and tumor synergistic therapy

Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.

Novel SERCA2 inhibitor Diphyllin displays anti-tumor effect in non-small cell lung cancer by promoting endoplasmic reticulum stress and mitochondrial dysfunction

Abnormal calcium signaling is associated with non-small cell lung cancer (NSCLC) malignant progression, poor survival and chemotherapy resistance. Targeting endoplasmic reticulum (ER) Ca2+ channels or pumps to block calcium uptake in the ER induces ER stress and concomitantly promotes mitochondrial calcium uptake, leading to mitochondrial dysfunction and ultimately inducing cell death. Here, we identified Diphyllin was a potential specific inhibitor of endoplasmic reticulum (ER) calcium-importing protein sarco/endoplasmic-reticulum Ca2+ ATPase 2 (SERCA2). In vitro and in vivo studies showed that Diphyllin increased NSCLC cell apoptosis, along with inhibition of cell proliferation and migration. Mechanistically, Diphyllin promoted ER stress by directly inhibiting SERCA2 activity and decreasing ER Ca2+ levels. At the same time, the accumulated Ca2+ in cytoplasm flowed into mitochondria to increase reactive oxygen species (ROS) and decrease mitochondrial membrane potential (MMP), leading to cytochrome C (Cyto C) release and mitochondrial dysfunction. In addition, we found that Diphyllin combined with cisplatin could have a synergistic anti-tumor effect in vitro and in vivo. Taken together, our results suggested that Diphyllin, as a potential novel inhibitor of SERCA2, exerts anti-tumor effects by blocking ER Ca2+ uptake and thereby promoting ER stress and mitochondrial dysfunction.