Star-shaped polymer micelles have good stability against dilution with water, showing promising application in drug delivery. In this work, biodegradable micelles made from star-shaped poly (ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) copolymer were prepared and used to deliver doxorubicin (Dox) in vitro and in vivo. First, an acrylated monomethoxy poly (ethylene glycol)-poly (ε-caprolactone) (MPEG-PCL) diblock copolymer was synthesized, which then self-assembled into micelles, with a core-shell structure, in water. Then, the double bonds at the end of the PCL blocks were conjugated together by radical polymerization, forming star-shaped MPEG-PCL (SSMPEG-PCL) micelles. These SSMPEG-PCL micelles were monodispersed (polydispersity index = 0.11), with mean diameter of ≈ 25 nm, in water. Blank SSMPEG-PCL micelles had little cytotoxicity and did not induce obvious hemolysis in vitro. The critical micelle concentration of the SSMPEG-PCL micelles was five times lower than that of the MPEG-PCL micelles. Dox was directly loaded into SSMPEG-PCL micelles by a pH-induced self-assembly method. Dox loading did not significantly affect the particle size of SSMPEG-PCL micelles. Dox-loaded SSMPEG-PCL (Dox/SSMPEG-PCL) micelles slowly released Dox in vitro, and the Dox release at pH 5.5 was faster than that at pH 7.0. Also, encapsulation of Dox in SSMPEG-PCL micelles enhanced the anticancer activity of Dox in vitro. Furthermore, the therapeutic efficiency of Dox/SSMPEG-PCL on colon cancer mouse model was evaluated. Dox/SSMPEG-PCL caused a more significant inhibitory effect on tumor growth than did free Dox or controls (P < 0.05), which indicated that Dox/SSMPEG-PCL had enhanced anticolon cancer activity in vivo. Analysis with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed that Dox/SSMPEG-PCL induced more tumor cell apoptosis than free Dox or controls. These results suggested that SSMPEG-PCL micelles have promising application in doxorubicin delivery for the enhancement of anticancer effect.

Purpose: To evaluate the treatment outcome of salvage concurrent radio-chemotherapy for patients with loco-recurrent esophageal cancer after surgery. Methods: 50 patients with loco-recurrent squamous-cell cancer after curative esophagectomy were retrospectively analyzed. Patients were treated with radiotherapy (median 60 Gy) combined with chemotherapy consisting of either 5-fluorouracil (5-FU) plus cisplatin (DDP) (R-FP group) or paclitaxel plus DDP (R-TP group). Results: The median follow-up period was 16.0 months. The 1-year and 3-year survival rates were 56% and 14%, respectively. The median progression-free survival (PFS) and overall survival (OS) time was 9.8 and 13.3 months respectively. There was no statistical significance of the PFS of the two groups. The OS (median 16.3 months) in the R-TP group was superior to that in the R-FP group (median: 9.8 months) (p = 0.012). Among the patients who had received ≥60 Gy irradiation dose, the median PFS (10.6 months) and OS (16.3 months) were significantly superior to the PFS (8.7 months) and OS (11.3 months) among those patients did not (all p < 0.05). Grade 3 treatment-related gastritis were observed in 6 (27.3%) and 7 (25%) patients in the R-FP and R-TP group respectively. By univariate survival analysis, the age (<60 years), TP regimen and higher irradiation dose might improve the OS of such patients in present study. Conclusions: For those patients with post-operative loco-recurrent squamous-cell esophageal carcinoma, radiotherapy combined with either FP or TP regimen chemotherapy was an effective salvage treatment. Younger age, treatment with the TP regimen and an irradiation dose ≥60 Gy might improve the patients’ treatment outcome.

Purpose: Low-dose radiotherapy (LDRT) may enhance the synergistic antitumor effect of combined immunotherapy and stereotactic body radiotherapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non–small cell lung cancer (NSCLC). Patients and Methods: This prospective phase I study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT [30 Gray (Gy)/3f] to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a programmed death-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAE) occurred in 96.6% (28/29) of patients [grade ≥ 3; 20.7% (6/29)]; 2 patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval, 3.7–16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging T-cell receptor clonotypes were associated with better PFS. Conclusions: The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with programmed death ligand-1–positive, driver gene–negative primary metastatic NSCLC.

Background: Data on the use of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation are limited. The current study aimed to assess the efficacy of ICIs in EGFR-mutant advanced NSCLC and explore the relevant influential factors.Materials and Methods: Relevant clinical data of EGFR-mutant NSCLC patients who had received ICIs were collected from multiple hospitals. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), and relevant influential factors.Results: A total of 122 advanced EGFR-mutant NSCLC patients were included in the final analysis. The total cohort had an objective response rate (ORR) of 32.0%, a median progression-free survival (mPFS) of 5.0 months, and a median overall survival (mOS) of 14.4 months. Among 96 patients with common EGFR mutations (19Del, 52 patients; L858R, 44 patients), those who were administered front-line ICI exhibited better survival benefits than those who received later-line ICI after disease progression on tyrosine kinase inhibitors (TKIs) treatment (mPFS: 7.2 months vs. 3.4 months, respectively, P < 0.0001; mOS: 15.1 months vs. 8.4 months, respectively, P <0.0001). Moreover, the efficacy of ICI-based combination therapy was better than that of ICI monotherapy (mPFS: 5.0 months vs. 2.2 months, respectively, P = 0.002; mOS: 14.4 months vs. 7.0 months, respectively, P = 0.001). Multivariate analysis showed that ICI-based combination therapy and front-line ICI administration after progression on EGFR-TKI were associated with significant improvements in both PFS and OS (P < 0.05). A high PD-L1 expression (tumor proportion score, TPS≥50%) and the EGFR L858R mutation were only significantly associated with a better PFS (P <0.05). A better Eastern Cooperative Oncology Group (ECOG) status was independently associated with a favorable OS (P <0.05).Conclusions: Taken together, combination immunotherapy in front-line was associated with improvement of survival in EGFR-mutant NSCLC patients post-TKI resistance. Further prospective studies with large sample sizes are required to identify the optimal combinatorial treatment strategy.

Background: Although immune checkpoint inhibitors (ICIs) provide unprecedented survival improvement for patients with advanced non-small cell lung cancer (NSCLC), disease progression inevitably occurs. After ICIs failure, limited data exist on whether ICI-based treatment beyond progression (TBP) may be beneficial to advanced NSCLC. This retrospective study aimed to evaluate the efficacy of this treatment approach in advanced NSCLC and identify potential beneficial factors. Methods: Patients with stage IV NSCLC who received ICI-based treatment after the failure of prior PD-1/PD-L1 inhibitor treatments (monotherapy or combination therapy) between January 2016 and July 2020 were enrolled. Their clinical characteristics and treatment procedures were collected, and the follow-up would be performed. Results: A total of 204 patients were included. All patients had disease progression after prior immunotherapy, with 49.5% (101/204) of patients presenting with new metastasis lesions and the rest 50.5% (103/204) of patients’ progression on originate lesions. Within the entire cohort, the median progression-free survival (PFS) and median overall survival (OS) of ICI-based TBP with prior immunotherapy were 5.0 months (95% CI: 4.5–5.5 months) and 15.7 months (95% CI: 14.7–16.8 months), respectively. The objective response rate (ORR) and disease control rate (DCR) were 9.3% and 74.0%, respectively. According to the multivariate analysis, ICI-based combination therapy [PFS: hazard ratio (HR), 0.48, 95% confidence interval (CI): 0.28–0.84, P=0.011] (OS: HR, 0.44, 95% CI: 0.23–0.85, P=0.014), not having targetable gene alterations (PFS: HR, 0.56, 95% CI: 0.40–0.79, P=0.001) (OS: HR, 0.57, 95% CI: 0.37–0.87, P=0.009), and good response to prior immunotherapy (PFS: HR, 0.36, 95% CI: 0.24–0.53, P<0.0001) (OS: HR, 0.31, 95% CI: 0.19–0.52, P<0.0001) were independently associated with improved PFS and OS. Moreover, disease progression due to appearances of new metastasis (OS: HR, 0.56, 95% CI: 0.37–0.84, P=0.005) was only associated with better OS. Conclusions: While the ORR in patients with advanced NSCLC receiving ICI-based TBP with prior immunotherapy was limited, the DCR was relatively high in our study which is encouraging. ICI-based treatment strategy may be a reasonable option for patients who progressed from prior immunotherapy. Further prospective studies on larger sample size are warranted.