Therapy For Non-small Cell Lung Cancer Research Articles

Engineering of Amphiphilic Erlotinib Analogue as Novel Nanomedicine for Non-Small Cell Lung Cancer Therapy

Engineering of Amphiphilic Erlotinib Analogue as Novel Nanomedicine for Non-Small Cell Lung Cancer Therapy

Stomatitis in patients receiving EGFR-targeted therapy for non-small cell lung cancer: A population-based cohort study across the United States.

406 Background: As the standard therapy for non-small cell lung cancer (NSCLC) patients expressing epidermal growth factor receptor (EGFR) mutations, EGFR tyrosine kinase inhibitors (EGFR-TKIs) possess advanced potency and survival outcomes in clinical trials. However, little is known for stomatitis as a potential adverse event. This study aimed to assess the risk of stomatitis among patients initiating different EGFR-targeted therapy for NSCLC in a real-world study. Methods: Patients diagnosed with NSCLC and newly initiated EGFR-targeted therapy between 2008 and 2023 were included from 92 healthcare organizations across the U.S., then matched to non-users via propensity scores on age, comorbidities, metastatic status, and previous history of anticancer therapies. The primary outcome, stomatitis, was retrieved by ICD-9 or ICD-10 codes. The risk of stomatitis in association with EGFR-TKI was evaluated using regression models to obtain the odds ratio (OR) with 95% confidence intervals (CIs). Subgroup analyses were conducted to identify the EGFR-TKI agents that were associated with the risk of stomatitis. Results: A total of 22,225 EGFR-TKI initiators were included, including 719 on gefitinib, 16,404 on erlotinib, 1,864 on afatinib, and 5,300 on osimertinib. EGFR-TKIs initiators presented with a significantly increased risk of stomatitis compared to non-users (n= 445 vs 367; OR=1.22; 95% CI=1.058-1.399). Among all EGFR-TKIs, erlotinib (n=316; OR=1.56; 95% CI=1.394-1.739), afatinib (n=81; OR=3.49; 95% CI=2.794-4.365), and osimertinib (n=95; OR=1.40; 95% CI=1.139-1.711) were significantly associated with an increased risk of stomatitis before propensity score matching. The risk of EGFR-TKI-associated stomatitis in those treated with afatinib was validated after propensity score matching (OR=2.23; 95% CI=1.528-3.393). Conclusions: The present study demonstrated a significantly high risk of stomatitis in relation to EGFR-targeted therapy for NSCLC. Multidisciplinary care involving oral medicine specialists and dentists is needed for patients with lung cancer.

Recent advances in neoantigen vaccines for treating non-small cell lung cancer.

The breakthrough of programmed cell death protein 1 (PD-1) blockade therapy has changed the clinical treatment of non-small cell lung cancer (NSCLC) in the past few years. The success of PD-1 blockade therapy has been attributed to high tumor mutation burden and high immunogenicity of lung cancer cells. To further improve the efficacy of NSCLC immunotherapy and overcome the resistance of lung cancer cells to immune checkpoint blockade, new approaches that enhance the active immune response, such as neoantigen vaccines and cellular-based therapies, are urgently required. Neoantigens are considered ideal targets for cancer immunotherapy because of their high immunogenicity and specificity. In this mini review, we first discuss the current advances in neoantigen vaccines for treating cancers and then review the results of preclinical studies and early-phase human clinical trials of neoantigen-based therapies for NSCLC. Finally, we focus on the identification of neoantigens in patients with NSCLC and review the candidate mutations reported by recent studies and our investigations. The review concludes that, in addition to immune checkpoint blockade, approaches targeting neoantigens are promising for improving the efficacy of NSCLC immunotherapy.

Novel Approach to Accelerate Lung Cancer Research: Lung-MAP and the Potential of Public-Private Partnerships.

The National Cancer Institute recently found that death rates for non-small cell lung cancer (NSCLC) have been reduced by over 6% overall in recent years. This reduction in mortality has been accompanied by an average increase in overall survival and largely credited to the therapeutic advancements for the effective treatment of NSCLC. Numerous molecular alterations have been identified in NSCLC that have enabled the development of new drugs capable of targeting these changes and efficiently kill cancerous cells. New treatments to modulate patients' immune systems have been shown to be effective in stimulating natural immune cells to have an improved anti-cancer effect. While these types of approaches to treat cancer are providing new options for patients, leadership from the Food and Drug Administration (FDA) recognized that the expansion of targeted therapy in NSCLC presented significant promise, but evaluation of the safety and efficacy of these new drugs would be slowed if new models for conducting clinical studies were not identified. Specifically, the FDA recommended that a comprehensive approach be implemented to identify the patients that are the best candidates for these, and other new treatments based upon the molecular characteristics of their tumors, and more efficiently conduct the clinical studies necessary to evaluate the safety and efficacy of new drugs. To address this growing challenge, leading lung cancer experts and stakeholders across academia, government, industry, and patient advocacy came together to design a clinical research approach that could serve as a sustainable infrastructure for new lung cancer treatments called the Lung Cancer Master Protocol.

Neoadjuvant Lorlatinib Induces Pathological Complete Response in Advanced ALK-Positive Lung Cancer: A Case Report.

BACKGROUND Chemotherapy has been the conventional treatment method for advanced non-small-cell lung cancer (NSCLC). Nevertheless, the identification and comprehension of oncogenic driver alterations have paved the way for targeted therapies, significantly enhancing patient outcomes. The management of locally advanced NSCLC that is positive for ALK presents a challenge due to the lack of reported randomized controlled trials. The efficacy of neoadjuvant and adjuvant targeted therapy in this context remains uncertain. CASE REPORT A 54-year-old man was diagnosed with stage IIIB (pT1N3M0) upper right lung adenocarcinoma carrying the EML4-ALK fusion gene. Clinically, the patient had multiple enlarged lymph nodes in the right hilum and mediastinum, with the largest measuring approximately 28×19 mm by CT scan and we found that the L4 lymph node was invaded by metastasis. Then, the patient received 1 cycle of chemotherapy with paclitaxel in combination with nedaplatin and subsequently received maintenance treatment involving lorlatinib. Two months later, clinical evaluations revealed progressive reduction of the lesions, especially the reduced size of the mediastinal lymph nodes. Therefore, the patient underwent thoracoscopic partial lobectomy and lymphadenectomy and achieved pathological complete response (pCR). After 3 months, a follow-up CT scan was similar to the first postoperative CT scan and no tumor was found. CONCLUSIONS This case demonstrates the potential advantage of lorlatinib as a neoadjuvant therapy in advanced ALK-positive NSCLC. It emphasizes the importance of identifying new therapeutic targets by next-generation sequencing (NGS) and implementing precise treatment strategies in clinical practice.

Hope and Challenges: Immunotherapy in EGFR-Mutant NSCLC Patients.

EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. Sadly, remission is transient, and no approved effective treatment options are available for EGFR-TKI-advanced EGFR-mutant NSCLCs. Although immunotherapy with immune checkpoint inhibitors (ICIs) induces sustained cancer remission in a subset of NSCLCs, ICI therapy exhibits limited activity in most EGFR-mutant NSCLCs. Mechanistically, the strong oncogenic EGFR signaling in EGFR-mutant NSCLCs contributes to a non-inflamed tumor immune microenvironment (TIME), characterized by a limited number of CD8+ T cell infiltration, a high number of regulatory CD4+ T cells, and an increased number of inactivated infiltrated T cells. Additionally, EGFR-mutant NSCLC patients are generally non-smokers with low levels of PD-L1 expression and tumor mutation burden. Promisingly, a small population of EGFR-mutant NSCLCs still durably respond to ICI therapy. The hope of ICI therapy from pre-clinical studies and clinical trials is reviewed in EGFR-mutant NSCLCs. The challenges of application ICI therapy in EGFR-mutant NSCLCs are also reviewed.

Tumor-infiltrating platelets promote the growth of lung adenocarcinoma

PurposePlatelets could promote tumor growth and metastasis. However, the role of platelets in different subtypes of non-small cell lung cancer (NSCLC) and platelet infiltration in local tumor tissue remain unclear. MethodsInitially, platelet infiltration in lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC) was estimated by CD41 expression using immunohistochemistry. Subsequently, co-incubation of NSCLC cell lines and platelets was performed to compare the ability of binding platelets. Subcutaneous tumor models were established to assess the ability of platelets to promote tumor growth. Then, RNA-seq data of NSCLC was used to identify differentially expressed genes and enriched pathways. Lastly, a clinical cohort comprising of ADC and SCC patients as well as meta-analysis was analyzed to compare the difference of coagulation associated clinical parameters. ResultsWe found high platelet infiltration in ADC, especially of advanced disease and metastases, whereas few platelets were observed in SCC. Moreover, ADC cell lines exhibited strong ability of binding platelets compared with SCC cell lines. Platelets could also promote the growth of ADC cell lines in vivo. Furthermore, coagulation cascades and fibrinogen were upregulated in ADC. And chemical inhibition of GPIIb/IIIa-fibrinogen axis reduced the binding of ADC cells and platelets. ADC patients were also in a hypercoagulable state characterized by higher d-dimer level and shorter clotting time. Finally, meta-analysis identified a higher risk of venous thromboembolism (VTE) in ADC patients and low molecular weight heparin (LMWH) treatment was effective at reducing this risk. ConclusionsThis study identified the differences of platelet infiltration and coagulation between ADC and SCC patients, which may inform the development of anticoagulation therapies for NSCLC.

E3 ligase TRIM28 promotes anti-PD-1 resistance in non-small cell lung cancer by enhancing the recruitment of myeloid-derived suppressor cells

BackgroundAlterations in several tripartite motif-containing (TRIM) family proteins have been implicated in the pathogenesis of lung cancer. TRIM28, a member of the TRIM E3 ligase family, has been associated with tumorigenesis, cell proliferation, and inflammation. However, little is known about TRIM28 expression and its role in the immune microenvironment of non-small cell lung cancer (NSCLC).MethodsWe assessed the clinical significance of TRIM28 in tissue microarrays and TCGA cohorts. We investigated the function of TRIM28 in syngeneic mouse tumor models, the KrasLSL−G12D/+; Tp53fl/fl (KP) mouse model, and humanized mice. Immune cell composition was analyzed using flow cytometry and immunohistochemistry.ResultsOur findings revealed a positive correlation between TRIM28 expression and the infiltration of suppressive myeloid-derived suppressor cells (MDSCs) in NSCLC. Moreover, silencing TRIM28 enhanced the efficacy of anti-PD-1 immunotherapy by reshaping the inflamed tumor microenvironment. Mechanistically, we demonstrated that TRIM28 could physically interact with receptor-interacting protein kinase 1 (RIPK1) and promote K63-linked ubiquitination of RIPK1, which is crucial for sustaining activation of the NF-κB pathway. Mutagenesis of the E3 ligase domain corroborated the essential role of E3 ligase activity in TRIM28-mediated NF-κB activation. Further experiments revealed that TRIM28 could upregulate the expression of CXCL1 by activating NF-κB signaling. CXCL1 could bind to CXCR2 on MDSCs and promote their migration to the tumor microenvironment. TRIM28 knockdown increased responsiveness to anti-PD-1 therapy in immunocompetent mice, characterized by increased CD8+T tumor-infiltrating lymphocytes and decreased MDSCs.ConclusionThe present study identified TRIM28 as a promoter of chemokine-driven recruitment of MDSCs through RIPK1-mediated NF-κB activation, leading to the suppression of infiltrating activated CD8+T cells and the development of anti-PD-1 resistance. Understanding the regulation of MDSC recruitment and function by TRIM28 provides crucial insights into the association between TRIM28 signaling and the development of an immunosuppressive tumor microenvironment. These insights may inform the development of combination therapies to enhance the effectiveness of immune checkpoint blockade therapy in NSCLC.

Discovery of 4-((3,4-dichlorophenyl)amino)-2-methylquinolin-6-ol derivatives as EGFR and HDAC dual inhibitors

In patients with non-small cell lung cancer (NSCLC), the standard therapy consists of selective tyrosine kinase inhibitors that target epidermal growth factor receptors (EGFR). Nonetheless, their clinical utility is primarily limited by the development of resistance to drugs. HDAC inhibitors have been shown in studies to reduce the level of EGFR that is expressed and downregulate the EGFR-induced phosphorylation of AKT and ERK. Therefore, dual inhibitors of EGFR and HDAC provide a potential approach as combination treatment synergistically inhibited the growth of NSCLC. Herein, we examined the EGFR inhibition effect of twenty compounds which designed and synthesized by us previously. Among them, compounds 12c and 12d exhibited powerful antiproliferative activity against the NCI–H1975 cell line with IC50 values of 0.48 ± 0.07 and 0.35 ± 0.02 μM, correspondingly. In cell-free kinase assays, both 12c and 12d demonstrated target-specific EGFR inhibition against wild type (EGFRwt). Furthermore, the expression of EGFR and phosphorylation of the EGF-induced pathways were significantly suppressed under the treatment of 12c and 12d. Besides, both histones H3 and H4 exhibited increased levels of acetylation following 12c and 12d treatment. The animal experiments shown that 12d could prevent the growth of tumor, inhibited the expression of EGFR and the phosphorylation levels of p70 S6K, AKT and p38 MAPK in vivo, and did not cause organ damage to the mice during the experiment.Overall, the results illustrated that compound 12c and 12d could serve as effective EGFR and HDAC dual inhibitors in NSCLC cells. Our work offers an alternative strategy for NSCLC therapy.

Concurrent Mutations in STK11 and KEAP1 Cause Treatment Resistance in KRAS Wild-type Non-small-cell Lung Cancer.

We herein report a patient with KRAS wild-type non-small-cell lung cancer (NSCLC) with concurrent STK11 and KEAP1 mutations. A 53-year-old man visited a local doctor with a complaint of left shoulder swelling and pain. He was diagnosed with NSCLC cT4N0M1c stage IVB. A comprehensive genome profile test revealed mutations in STK11 and KEAP1 but no KRAS mutations. The patient was refractory to radiotherapy, immunotherapy, and chemotherapy. Thus, STK11 and KEAP1 mutations can be considered resistance mutations that confer resistance to various anticancer therapies in KRAS wild-type NSCLC.

T Cell Invigoration is Associated with the Clinical Response to Anti-PD-1-Based Immunotherapy in Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have been developed for clinical application and proven effective for non-small cell lung cancer (NSCLC). Blockade of the programmed cell death 1 (PD-1) protein can partially reinvigorate circulating exhausted-phenotype CD8+ T cells (Tex cells) in preclinical models, however the clinical implication in anti-PD-1-based immunotherapy in NSCLC is unknown. Serum specimens were obtained before and during treatment from 145 patients with NSCLC patients who received anti-PD-1 treatment and their prognoses were followed-up. Indicators such as cellsubpopulations, T cell invigoration were detected by clinical laboratory testing. Survival curves were estimated by the Kaplan-Meier method, Cox regression analysis was used to identify factors associated with prognoses of NSCLC patients. The expressions of Ki-67 in PD-1+/CD8+ T cells in most NSCLC patients (97 of 145 cases) increased after treatment. The responding Ki-67+/CD8+ T cell population was mainly CD45RAlo CD27hi, containing cells with high expression of CTLA-4, PD-1, and 2B4 and low expression of NKG2-D (P < 0.0001). The maximum fold change of Ki-67+/PD-1+/CD8+T cells in treatment cycles and the tumor burden determined by imaging may be associated with survival. Patients with higher Ki-67 expression on PD-1+CD8+ T-cells (pretreatment) had statistically significant increased progression-free survival (PFS). A Ki-67 expression to tumor burden ratio greater than 0.6 at the 1st cycle of anti-PD-1 immunotherapy was associated with improvement of PFS and overall survival (P < 0.05). Activation of circulating Tex cells before or during therapy related to tumor burden may be associated with clinical efficacy of anti-PD-1 immune therapy in NSCLC.

High endothelial venules predict response to PD-1 inhibitors combined with anti-angiogenesis therapy in NSCLC

Tumor-associated high endothelial venules (TA-HEVs) mediate lymphocyte entry into tumors. Therefore, combined anti-angiogenesis therapy and programmed death-1 (PD-1) inhibitors might stimulate tumor immunity. This study will explore the TA-HEVs and real-world data of the combination therapy in non-small cell lung cancer (NSCLC). Firstly, we found a certain relationship between HEVs and immune effector cells by multiple immunofluorescence staining. We then analyzed the efficacy of immunotherapy combined with anti-angiogenesis therapy in advanced NSCLC patients by collecting real-world clinical data. Finally, we explored the predictive value of HEVs in combination therapy by analyzing pre-treatment pathological slides of patients with multiple immunofluorescence and RNA sequencing. Immunofluorescence staining of high endothelial venules (PNAd+) reveals that the frequency of HEVs is positively correlated with tumor-infiltrating stem-like CD8+ T cells (TCF-1+PD-1+) in the TME of advanced NSCLC patients (P = 0.0221). We retrospectively analyzed the efficacy of 96 patients with advanced NSCLC who received PD-1 inhibitors combined with anti-angiogenesis therapy in the real-world. The median PFS of patients combined with anti-angiogenesis therapy was longer than that of patients without anti-angiogenesis therapy (9.7 vs 8.6 months, P = 0.041). Multiple immunofluorescence staining of tumor biopsies before treatment from 14 patients with advanced NSCLC reveals that PNAd+ is predictive of better response and survival upon PD-1 inhibitors combined with anti-angiogenesis therapy (P = 0.0274). In addition, we collected peripheral blood from an effective group of patients for RNA sequencing and found that immune cells activation-related gene expression scores were higher. Combined anti-angiogenic and anti-PD-1 therapy stimulates tumor immunity through TA-HEVs formation. TA-HEVs not only mediate immune cell entry into tumors, but also are associated with the efficacy of PD-1 inhibitors and anti-angiogenesis therapy in NSCLC.

Taxifolin Inhibits the Growth of Non-Small-Cell Lung Cancer via Downregulating Genes Displaying Novel and Robust Associations with Immune Evasion Factors.

Using an LL2 cell-based syngeneic mouse LC model, taxifolin suppressed allografts along with the appearance of 578 differentially expressed genes (DEGs). These DEGs were associated with enhancement of processes related to the extracellular matrix and lymphocyte chemotaxis as well as the reduction in pathways relevant to cell proliferation. From these DEGs, we formulated 12-gene (TxflSig) and 7-gene (TxflSig1) panels; both predicted response to ICB (immune checkpoint blockade) therapy more effectively in non-small-cell lung cancer (NSCLC) than numerous well-established ICB biomarkers, including PD-L1. In both panels, the mouse counterparts of ITGAL, ITGAX, and TMEM119 genes were downregulated by taxifolin. They were strongly associated with immune suppression in LC, evidenced by their robust correlations with the major immunosuppressive cell types (MDSC, Treg, and macrophage) and multiple immune checkpoints in NSCLC and across multiple human cancer types. ITGAL, ITGAX, and IIT (ITGAL-ITGAX-TMEM119) effectively predicted NSCLC's response to ICB therapy; IIT stratified the mortality risk of NSCLC. The stromal expressions of ITGAL and ITGAX, together with tumor expression of TMEM119 in NSCLC, were demonstrated. Collectively, we report multiple novel ICB biomarkers-TxflSig, TxflSig1, IIT, ITGAL, and ITGAX-and taxifolin-derived attenuation of immunosuppressive activities in NSCLC, suggesting the inclusion of taxifolin in ICB therapies for NSCLC.

AI-Derived CT Body Composition in Advanced Non-Small Cell Lung Cancer: A Multicohort Study

The relationship between body composition (BC) and cancer outcomes is complex and incompletely understood. Previous research in non-small cell lung cancer (NSCLC) has been limited to small single-institution studies, which have yielded inconsistent results. We conducted a comprehensive multicohort analysis to evaluate the impact of BC on overall survival (OS) in advanced NSCLC treated with systemic therapy. The analysis included data from the phase I/II CP1108 study (NSCLC Durvalumab cohort) and the chemotherapy arm of the phase III MYSTIC trial. We also analyzed data from Dana-Farber Cancer Institute (DFCI) cohorts receiving immunotherapy alone or in combination with chemotherapy. Baseline and follow-up (FU) CT scans were collected and analyzed using deep neural networks for automatic L3 slice selection and body compartment segmentation (skeletal muscle [SM], subcutaneous adipose tissue [SAT], and visceral adipose tissue [VAT]). We compared OS based on baseline BC measures or their change at the first FU scan. The impact of sarcopenia at baseline was evaluated in association with the delta metrics. A total of 1865 NSCLC patients were analyzed, of which 222 were treated on CP1108, 257 were treated on MYSTIC, 870 received IO monotherapy at DFCI (DFCI-IO), and 516 received chemoimmunotherapy at DFCI (DFCI-CIO). The median ages were 65, 63, 66, and 65, respectively. A loss in SM mass >5%, as indicated by a change in L3 SM area, was significantly associated with poorer OS across all patient groups (median [months]: 5 vs. 19; p<0.001 for CP1108, 11 vs. 14; p = 0.03 for MYSTIC, 11 vs. 17; p<0.001 for DFCI-IO, and 12 vs. 22; p<0.001 for DFCI-CIO). This effect was driven by male patients, with a non-significant association (p>0.5) among female patients in the MYSTIC and DFCI-CIO cohorts. An increase in SAT density >5%, as quantified by the average CT attenuation in HU of the SAT compartment, was significantly linked to poorer OS in three patient groups (median [months]: 4 vs. 19; p<0.001 for CP1108, 10 vs. 17; p<0.001 for DFCI-IO, and 12 vs. 20; p = 0.003 for DFCI-CIO). This was primarily observed among female patients, with a non-significant association (p>0.5) among male patients in the DFCI-CIO cohort. On subgroup analysis, loss in SM mass had an impact on OS in patients with baseline sarcopenia (median [months] 5 vs. 22; p<0.001 for CP1108, 5 vs. 12; p = 0.03 for MYSTIC, 11 vs. 17; p<0.001 for DFCI IO, and 9 vs. 17; p = 0.003 for DFCI-CIO). Conversely, no association was observed between change in SM mass and OS in patients without sarcopenia at baseline in the MYSTIC and DFCI-IO cohorts. Sarcopenia and loss in SM mass during systemic therapy for NSCLC are markers of poor outcome, especially in male patients. SAT density changes are also strongly associated with prognosis, particularly in female patients. Automated CT-derived BC measurements should be considered along with other risk factors in determining lung cancer prognosis and ability to tolerate oncologic treatments.

Dosimetric Predictors for Acute Esophagitis during Radiation Therapy for Lung Cancer: An Update of a Large Statewide Observational Study

Acute esophagitis remains a clinical challenge during the treatment of locally advanced non-small cell lung cancer (NSCLC). Here, we analyze the dosimetric and patient-level characteristics associated with acute grade 2+ and 3+ esophagitis in patients undergoing radiation therapy for NSCLC across a statewide consortium. Demographic, dosimetric, and acute toxicity data were prospectively collected for patients undergoing definitive radiation therapy +/- chemotherapy for stage II-III NSCLC from 2012-2022 across the Michigan Radiation Oncology Quality Consortium (MROQC). Logistic regression models were used to characterize the risk of grade 2+ and 3+ esophagitis as a function of dosimetric and clinical covariates. Multivariate regression models were fitted to predict the 50% risk of grade 2 esophagitis or 3% risk of grade 3 esophagitis at each dose value. Of 1760 patients evaluated, 84.2% had stage III disease and 85.3% received concurrent chemotherapy. 79.2% of patients had an ECOG performance status ≤1. Rates of acute grade 2+ and 3+ esophagitis were 48.4% and 2.2%, respectively. On multivariate analyses, performance status, mean esophageal dose and esophageal D2cc were significantly associated with grade 2+ and 3+ esophagitis. Concurrent chemotherapy was associated with grade 2+ but not grade 3+ esophagitis. Dose-response relationships were modeled for grade 2+ and 3+ esophagitis by mean esophageal dose and esophageal D2cc, stratified by performance status and/or receipt of concurrent chemotherapy. For all patients, mean esophageal dose of 29 Gy and esophageal D2cc of 61 Gy corresponded to a 3% risk of acute grade 3+ esophagitis. For patients receiving chemotherapy, mean esophageal dose of 22 Gy and esophageal D2cc of 49.5 Gy corresponded to a 50% risk of acute grade 2+ esophagitis. Performance status, concurrent chemotherapy, mean esophageal dose and esophageal D2cc are associated with acute esophagitis during definitive treatment of NSCLC. Models that quantitatively account for these factors can be useful in individualizing radiation plans. Mean esophageal dose of 29 Gy and esophageal D2cc of 61 Gy corresponded to a 3% risk of acute grade 3+ esophagitis and merit consideration as contemporary treatment planning constraints.

A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer.

Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.

Non-small cell lung cancers (NSCLCs) oncolysis using coxsackievirus B5 and synergistic DNA-damage response inhibitors

With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.

Efficacy, safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China (CTONG1702-Arm 8): a multi-center, single-arm, phase 2 trial

Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200mg (n=15) or 300mg (n=15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200mg, 80%; 300mg, 60%). The median progression-free survival was 12.9 months (200mg, 15.8 months; 300mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200mg: 60%; 300mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Chinese Thoracic Oncology Group (CTONG).

Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling.

The extracellular matrix (ECM) has been strongly correlated with cancer progression in various tumor types. However, the specific mechanisms underlying ECM-associated tumor behaviors remain unclear. In this study, we found an enriched distribution of fibrin in tumor tissues obtained from high-grade non-small cell lung cancer (NSCLC) patients. For further investigation, we established an in vitro 3D culture system using fibrin gel and found that NSCLC cells grown in this system exhibited increased stemness and tumorigenesis. Mechanistically, we demonstrated that fibrin facilitated the activation of the phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling pathway through integrin β1. Furthermore, we found that blocking integrin β1 signals enhanced the tumor suppressive effects of chemotherapy, providing a novel approach for clinical therapy for NSCLC.

Pharmacological Ascorbate Elicits Anti-Cancer Activities against Non-Small Cell Lung Cancer through Hydrogen-Peroxide-Induced-DNA-Damage.

Non-small cell lung cancer (NSCLC) poses a significant global health burden with unsatisfactory survival rates, despite advancements in diagnostic and therapeutic modalities. Novel therapeutic approaches are urgently required to improve patient outcomes. Pharmacological ascorbate (P-AscH-; ascorbate at millimolar concentration in plasma) emerged as a potential candidate for cancer therapy for recent decades. In this present study, we explore the anti-cancer effects of P-AscH- on NSCLC and elucidate its underlying mechanisms. P-AscH- treatment induces formation of cellular oxidative distress; disrupts cellular bioenergetics; and leads to induction of apoptotic cell death and ultimately reduction in clonogenic survival. Remarkably, DNA and DNA damage response machineries are identified as vulnerable targets for P-AscH- in NSCLC therapy. Treatments with P-AscH- increase the formation of DNA damage and replication stress markers while inducing mislocalization of DNA repair machineries. The cytotoxic and genotoxic effects of P-AscH- on NSCLC were reversed by co-treatment with catalase, highlighting the roles of extracellular hydrogen peroxide in anti-cancer activities of P-AscH-. The data from this current research advance our understanding of P-AscH- in cancer treatment and support its potential clinical use as a therapeutic option for NSCLC therapy.