Search

Chimeric antigen receptor (CAR)-modified T (CAR-T) cell therapy has been proven to be a powerful tool for the treatment of cancer, however, the limits are obvious, especially for solid tumors. Therefore, constantly optimizing the structure of CAR to improve its therapeutic effect is necessary. In this study, we generated three different third-generation CARs targeting IL13Rα2, with the same scFv, but different transmembrane domains (TMDs) from CD4, CD8 or CD28 (IL13-CD4TM-28.BB.ζ, IL13-CD8TM-28.BB.ζ and IL13-CD28TM-28.BB.ζ). CARs were transduced into primary T cells using retroviruses. The anti-GBM efficacy of CAR-T cells was monitored by flow cytometry and real-time cell analysis (RTCA) in vitro and examined in two xenograft mouse models. The differentially expressed genes related to different anti-GBM activity were screened by high throughput RNA sequencing. We observed that T cells transduced with these three CARs have similar anti-tumor activity when co-cultured with U373 cells which expressed higher IL13Rα2 but exhibited different anti-tumor activity when co-cultured with U251 cells that expressed lower IL13Rα2. All the three groups of CAR-T cells can be activated by U373 cells, but only IL13-CD28TM-28.BB.ζ CAR-T cells could be activated and expressed increased IFN-γ after co-culturing with U251 cells. IL13-CD28TM-28.BB.ζ CAR-T cells exhibited the best anti-tumor activity in xenograft mouse models which can infiltrate into the tumors. The superior anti-tumor efficacy of IL13-CD28TM-28.BB.ζ CAR-T cells was partially owing to differentially expressed extracellular assembly, extracellular matrix, cell migration and adhesion-related genes which contribute to the lower activation threshold, increased cell proliferation, and elevated migration capacity. [ABSTRACT FROM AUTHOR]

The malignancy of non-small cell lung cancer (NSCLC) is largely due to its invasion. Hence, prevention of the cancer cell invasion, which is essentially regulated by vascular endothelial growth factor A (VEGF-A), is substantially critical for a successful treatment for NSCLC. Here, we showed that compared to other cancers, NSCLC had a significant higher ratio of VEGF-A protein vs mRNA, and significantly lower levels of miR-497, suggesting presence of a post-transcriptional control of VEGF-A in NSCLC different from other cancers. Compared with paired normal lung tissue, NSCLC expressed lower levels of miR-497 and higher levels of VEGF-A. Moreover, the levels of miR-497 and VEGF-A were inversely correlated in NSCLC specimen. Bioinformatics analyses showed that miR-497 bound to 3′-UTR of VEGF-A mRNA in NSCLC lines to inhibit its translation. Overexpression of miR-497 in NSCLC lines decreased VEGF-A protein, while depletion of miR-497 in NSCLC lines increased VEGF-A protein. However, modification of miR-497 levels in NSCLC lines did not alter VEGF-A mRNA levels. Overexpression of miR-497 in NSCLC lines inhibited cell growth and invasion, while depletion of miR-497 in NSCLC lines increased cell growth and invasion. Together, our data demonstrate a previously unappreciated role for miR-497 in suppression of VEGF-A-mediated NSCLC cancer cell growth and invasion. [ABSTRACT FROM AUTHOR]

[Display omitted] Nanoparticle polymeric micellar paclitaxel (Pm-Pac) has been demonstrated to have a safety profile and efficacy in advanced non-small cell lung cancer (NSCLC) patients. However, whether Pm-Pac could prolong overall survival (OS) for specific advanced NSCLC patients is still unknown. In the present study, a total of 448 patients were randomly assigned (2:1) by the permuted block algorithm to receive Pm-Pac plus cisplatin or solvent-based paclitaxel (Sb-Pac) plus cisplatin (NCT02667743). We performed subgroup analysis based on metastatic status to identify the potential benefit patients. Our results indicated that the metastatic profiles were similar between the Sb-Pac plus cisplatin cohort and the Pm-Pac plus cisplatin cohort. Several subgroups (Metastases = 2, Bone metastasis, No pleural metastasis, etc.) were observed to have increased progression-free survival (PFS) due to Pm-Pac plus cisplatin. Importantly, we found the first evidence that Pm-Pac potentially prolonged OS with a favourable safety profile in NSCLC patients without pleural metastasis. Collectively, this study provides a novel perspective on the development of nanomedicine to investigate chemotherapeutic efficacy and toxicity and provides the first clinical evidence that Pm-Pac administration not only prolongs PFS but also prolongs OS with a favourable safety profile in advanced NSCLC patients without pleural metastasis. [ABSTRACT FROM AUTHOR]

Background: Anlotinib is a targeted therapy indicated for some malignancies, including advanced non-small cell lung cancer (NSCLC). However, noninvasive biomarkers for identifying patients who will benefit from this disease remain lacking. Methods: Here, we investigated the potential of small extracellular vesicle (sEV) microRNAs (miRNAs) as predictive biomarkers for anlotinib efficacy. A total of 20 advanced NSCLC patients were enrolled. Patients were classified as having stable disease (SD) or progressive disease (PD) after the initial efficacy assessment. Results: Seven differentially expressed miRNAs (DEMs) were identified. Among them, miR-941 was significantly upregulated in the PD group, while the others were downregulated. Furthermore, these six downregulated miRNAs (miR-30a-3p, miR-150-5p, miR-122-5p, miR-10b-5p, miR-92a-3p, and miR-150-3p) were more pronounced in nonsmoking patients. Conclusions: It was found that sEV miRNAs have the potential to predict the benefit of anlotinib. [ABSTRACT FROM AUTHOR]

Background: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. Methods: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. Results: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. Conclusion: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. Trial registration: NCT04507906 August 11, 2020. [ABSTRACT FROM AUTHOR]

Introduction: Durvalumab is a check‐point inhibitor against programmed death ligand‐1 (PD‐L1), and anlotinib is a new orally administered multitarget tyrosine kinase inhibitor (TKI). Both agents have been approved in China. Preclinical and clinical trials have suggested that antiangiogenic therapy has the potential to alleviate immunosuppression and showed synergetic effect when combined with ICIs. However, it is unclear that whether this combination is effective when initiated as maintenance treatment in ES‐SCLC patients. Methods: This is a multicenter, randomized, phase II study. A total of 64 eligible patients who do not experience disease progression after four cycles platinum‐based chemotherapy combined with durvalumab will be randomized to durvalumab with anlotinib or durvalumab alone until disease progression, withdrawal of consent, or unacceptable toxicity. The primary endpoint is PFS (from randomization); secondary endpoint was OS and PFS (from diagnosis), objective response rate (ORR); disease control rate (DCR) and duration of response (DOR), safety and tolerability assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Discussion: We conduct a phase II study to investigate the safety and efficacy of durvalumab combined with anlotinib as maintenance treatment in ES‐SCLC patients. [ABSTRACT FROM AUTHOR]

Introduction: Lung cancer with extrathoracic metastases is classified as M1c. However, extrathoracic metastases can be further classified into different patterns. The purpose of this study was to analyze the survival differences between different patterns of extrathoracic metastases in patients with stage M1c lung adenocarcinoma after receiving immunotherapy. Materials and methods: This study included 160 stage M1c lung adenocarcinoma patients and treated with immunotherapy. The enrolled patients were divided into two groups: those with multiple extrathoracic metastases alone (EM group) and those with simultaneous multiple extrathoracic and intrathoracic metastases (EIM group). Progression-free survival (PFS) and overall survival (OS) were evaluated. Results: The median PFS and OS in the whole group were 7.7 months and 25.4 months, respectively. The patients in the EM group show better PFS (13.0 months vs. 5.0 months; hazard ratio [HR] = 0.462, 95% confidence interval [CI] 0.317–0.673, P < 0.0001) and OS (35.0 months vs. 18.9 months; HR 0.592, 95% CI 0.380–0.922, P = 0.019) compared with the EIM group. Furthermore, in patients with lung adenocarcinoma with simultaneous extrathoracic and intrathoracic metastases who received immunotherapy, immunotherapy combined with chemotherapy has better PFS and OS than immunotherapy alone. There was no difference between immunotherapy alone or combined with chemotherapy in patients with lung adenocarcinoma with extrathoracic metastasis alone. Conclusion: The different patterns of extrathoracic metastasis were related to the efficacy and prognosis of immunotherapy in M1c cohort. In addition, patients with simultaneous extrathoracic and intrathoracic metastases were more recommended to choose immunotherapy in combination with chemotherapy rather than immunotherapy alone. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy against both B-cell malignancies and some types of solid tumors. Interleukin (IL) -15 is an important immune stimulator that may provide ideal long-term persistent CAR-T cells. However, higher base line or peak serum IL-15 levels are also related to severe toxicity, such as cytokine release syndrome (CRS), graft-versus-host disease (GVHD), and neurotoxicity.Methods: We successfully constructed CD19 specific armored CAR-T cells overexpressing IL-I5 and IL-15 receptor alpha (IL-15Ra). In vitro cell differentiation and viability were monitored by flow cytometry, and an in vivo xenograft mouse models was used to evaluate the anti-tumor efficiency and liver damage of CAR-T cells.Results: CAR-T cells overexpressing IL-15 alone demonstrated enhanced viability, retarded exhaustion in vitro and superior tumor-inhibitory effects in vivo. However, these tumor-free mice had lower survival rates, with serious liver injuries, as a possible result of toxicity. As expected, CAR-T cells overexpressing IL-15 combined with IL-15Ra had reduced CD132 expression and released fewer cytokines (IFNγ, IL-2 and IL-15) in vitro, as well as had the tendency to improve mouse survival via repressing the growth of tumor cells and keeping livers healthier compared to CAR-IL-15 T cells.Conclusions: These results indicated the importance of IL-15 in enhancing T cells persistence and IL-15Ra in reducing the adverse effects of IL-15, with superior tumor retardation during CAR-T therapy. This study paves the way for the rapid exploitation of IL-15 in adoptive cell therapy in the future. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the treatment response, survival profiles, prognostic factors and adverse events of anlotinib in treating advanced non-small cell lung cancer (NSCLC) patients.Materials and Methods: Totally, 158 advanced NSCLC patients were included in this retrospective study. All patients received anlotinib treatment until disease progression or intolerance: Administrated orally 12 mg/d for 2 weeks then discontinued for 1 week (3 weeks as a treatment cycle). Furthermore, treatment response, adverse events, and survivals were evaluated.Results: After 2 treatment cycles, no (0%) patients achieved complete response (CR), 7 (5.0%) patients achieved partial response (PR), 112 (80.0%) patients achieved standard deviation (SD), and 21 (15.0%) patients achieved progressive disease (PD), resulting in objective response rate (ORR) of 5.0% and disease control rate (DCR) of 85.0%. After 4 treatment cycles, no (0%) patients achieved CR, 3 (4.3%) patients achieved PR, 51 (74.0%) patients achieved SD, and 15 (21.7%) patients achieved PD, resulting in ORR of 4.3% and DCR of 78.3%. For survivals, the median progression-free (PFS) was 3.7 months (95% confidence interval [CI]: 2.7-4.7 months), and the median overall survival (OS) was 12.4 months (95% CI: 9.4-15.3 months). Subsequently, multivariate Cox's regression analyses illuminate that histological type (adenosquamous carcinoma vs. adenocarcinoma) and other mutation apart from epidermal growth factor receptor independently predicted shorter PFS; meanwhile, history of smoke and brain metastases independently predicted decreased OS. Regarding safety, most of the adverse events were at mild grade.Conclusion: Anlotinib displays good efficacy and well-tolerant safety profiles in the treatment of advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Background The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. Methods This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. Results Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21–95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively. Conclusions The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting. [ABSTRACT FROM AUTHOR]

Background: Dacomitinib is a second-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). ARCHER-1050 showed that this agent can improve progression-free survival and overall survival in advanced non-small cell lung cancer patients with sensitive EGFR mutation compared to gefitinib. However, it is unclear whether dacomitinib is effective in patients with sensitizing uncommon EGFR mutations in exon 18-21. The aim of this study is to investigate the safety and efficacy of dacomitinib in these patients.Methods: This is a single arm, prospective, open label and phase II trial. Sample size will be calculated by a minimax two-stage design method based on the following parameters: α = 0.075, 1-β = 0.9, P0 = 0.20, P1 = 0.45 and a dropout rate of 10%. A total of 30 eligible patients will be included. Patients will receive continuous oral therapy with dacomitinib (45 mg/day) until disease progression, withdrawal of consent, or unacceptable toxicity, whichever occurs first. The primary endpoint is objective response rate (ORR) per RECIST version 1.1, as assessed by investigators' review. The second endpoint is disease control rate (DCR), PFS, OS, and safety.Discussion: We conduct a single arm, phase II study to investigate the safety and efficacy of dacomitinib in advanced NSCLC patients with sensitizing uncommon EGFR mutations. The results of the DANCE study will provide new data regarding efficacy and safety of these patients.Trial Registration: NCT04504071. [ABSTRACT FROM AUTHOR]

Abstract: To identify cancer-related proteins, we used isobaric tags in a relative and absolute quantitation (iTRAQ) proteomic approach and SWATH™ quantification approach to analyze the secretome of an isogenic pair of highly metastatic and low metastatic non-small-cell lung cancer (NSCLC) cell lines. In addition, we compared two groups of pooled serum samples (12 early-stage and 12 late-stage patients) to mine data for candidates screened by iTRAQ-labeled proteomic analysis. A total of 110 proteins and 71 proteins were observed to be significantly differentially expressed in the cell line secretome and NSCLC sera, respectively. Among these proteins, CD109 was found to be highly expressed in both the highly metastatic cell line secretome and the group of late-stage patients. A sandwich ELISA assay also demonstrated an elevation of serum CD109 levels in individual NSCLC patients (n=30) compared with healthy subjects (n=19). Furthermore, CD109 displayed higher expression in lung cancer tissues compared with their matched noncancerous lung tissues (n=72). In addition, the knockdown of CD109 influenced several NSCLC cell bio-functions, for instance, depressing cell growth, affecting cell cycle phases. These phenomena suggest that CD109 plays a critical role in NSCLC progression. Biological significance: We simultaneously applied two quantitative proteomic approaches—iTRAQ-labeling and SWATH™—to analyze the secretome of metastatic cell lines, in order to explore the cancer-associated proteins in conditioned media. In this study, our results indicate that CD109 plays a critical role in non-small-cell lung cancer (NSCLC) progression, and is overexpressed in advanced NSCLC. [Copyright &y& Elsevier]

Although crizotinib has demonstrated promising efficacy and acceptable toxicity in patients with advanced non-small cell lung cancer ( NSCLC), the available evidence in Chinese populations is currently limited. This study compared the progression-free survival ( PFS) of Chinese patients with anaplastic lymphoma kinase ( ALK)-positive, advanced lung adenocarcinoma who received first-line crizotinib therapy with that of patients who received first-line standard chemotherapy, and also the PFS benefit of first-line versus second-line crizotinib treatment. Data on 80 patients with ALK-positive, advanced lung adenocarcinoma who received crizotinib or standard chemotherapy as first-line treatments between June 2013 and December 2014 were retrospectively collected; 26 of the patients received crizotinib as second-line therapy after progressive disease ( PD) occurred on first-line chemotherapy. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors ( RECIST), version 1.1. The median PFS was 13.3 months (95% CI: 6.5-20.0 months) in patients who received first-line crizotinib as compared with 5.4 months (95% CI: 4.4-6.5 months) in patients who received first-line standard chemotherapy (adjusted hazard ratio for progression or death with crizotinib, 0.20; 95% CI: 0.11-0.36; P < 0.001). In patients who received second-line crizotinib therapy, the median PFS was 9.9 months (95% CI: 6.4-13.4 months). The difference between first-line and second-line crizotinib treatment was not statistically significant (adjusted hazard ratio for progression, 0.56; 95% CI: 0.29-1.11; P = 0.092). Thus, there was a significant PFS benefit of first-line crizotinib versus first-line standard chemotherapy in Chinese patients with ALK-positive lung adenocarcinoma. Additionally, crizotinib showed promising efficacy in patients who received it as second-line therapy after PD had occurred on first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Background As it is difficult to obtain enough histopathological data for epidermal growth factor receptor ( EGFR) gene detection, it is necessary for us to explore how to perform EGFR-tyrosine kinase inhibitor ( TKI) therapy in patients with unknown EGFR gene mutations. Methods We analyzed the efficacy of Gefitinib treatment and the clinical characteristics of 214 patients with stage IV lung adenocarcinoma. Results Objective response rates ( ORR) and overall survival (OS) of women were higher than men; ORR of patients with rash, diarrhea, or rash associated with diarrhea, was higher than patients without those side effects. Progression-free survival ( PFS) of patients with performance status ( PS) scores of 1, 2, and 3 points was 8.0 ± 1.699, 7.3 ± 0.419, and 6.0 ± 2.010, respectively; OS was 26.0 ± 1.536, 16.3 ± 1.262, and 14.3 ± 2.389, respectively. PFS and OS of patients with rash and diarrhea were better than for those without these side effects. In males, the PFS of patients >65 years old versus ≤65 years old was 13.0 ± 2.7 months versus 5.5 ± 0.197 months, respectively. Multivariate analysis showed that PS score, diarrhea, and rash affected the patients' PFS, while gender, PS score, and rash affected the patients' OS. Conclusions In patients with stage IV lung adenocarcinoma and unknown EGFR gene mutations treated with Gefitinib, our findings suggest a better prognosis for female patients and those with low PS scores. [ABSTRACT FROM AUTHOR]

Anlotinib is a multitargeted antiangiogenic drug, and its clinical predictor for responsive non‐small cell lung cancer (NSCLC) patients is still elusive. Here, tumor‐specific target capture is used to profile the circulating DNA of ALTER0303 (evaluating NSCLC clinical antitumor efficacy through anlotinib therapy) study participants. The results indicate that patients receiving no benefit can be mainly excluded via analysis of ARID1A and BRCA2 genetic profiling. For patients with no durable benefit and durable clinical benefit patients, three predictors: germline and somatic mutation burden (G+S MB), nonsynonymous and synonymous mutation burden (N+S MB), and unfavorable mutation score of circulating DNA profiling are identified. Through integrating the advantages and disadvantages of three independent predictors, the tumor mutation index (TMI) is established as a prediction model and the patients who are very likely to benefit more from anlotinib therapy are identified. Furthermore, the IDH1exon 4 mutation is identified as an unfavorable factor for anlotinib therapy under TMI‐based stratification, and the TMI plus IDH1exon 4 mutation status potentially predicts response to anlotinib. Collectively, this study provides a circulating DNA sequencing–based stratification method for identifying anlotinib responders via a noninvasive approach, and thus potentially improves the clinical outcome of NSCLC patients receiving third‐line therapy. [ABSTRACT FROM AUTHOR]