First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors.

BACKGROUND: QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. METHODS: In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. RESULTS: Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3-not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. CONCLUSIONS: QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Treatment Patterns and Outcomes in Chinese Patients with Gastric Cancer by HER2 Status: A Noninterventional Registry Study (EVIDENCE).

BACKGROUND: Real-world safety and effectiveness data for trastuzumab plus chemotherapy treatment of patients with HER2-positive metastatic gastric cancer (mGC) in China are lacking. PATIENTS AND METHODS: EVIDENCE was a prospective, multicenter, noninterventional registry study evaluating the safety and effectiveness of trastuzumab in five cohorts of Chinese patients with gastric cancer, stratified by HER2 status and trastuzumab treatment. Effectiveness was analyzed for cohorts I (HER2-positive, trastuzumab treated), II (HER2-positive, trastuzumab untreated), and IV (HER2-negative, trastuzumab untreated); trastuzumab-related adverse events (AEs) were analyzed for cohort I. RESULTS: Cohorts I, II, and IV included 174, 113, and 422 patients, respectively. Most patients received first-line chemotherapy (87.6%). Median overall survival (OS1) for first-line treatment was 22.3, 17.2, and 17.4 months in cohorts I, II, and IV, respectively. After excluding patients who had surgery, respective median OS1 was 19.9, 15.3, and 12.9 months. Respective first-line progression-free survival (PFS1) was 8.2, 6.9, and 6.2 months; and respective first-line response rates (RR) were 51.7%, 18.4%, and 32.8%. Cohort I was significantly favored over cohort II for propensity score-matched first-line median OS1 (hazard ratio [HR], 0.61), PFS1 (HR, 0.64), and RR (odds ratio, 4.93). Trastuzumab-related AEs, grade 3-5 AEs, serious AEs, and AEs with a fatal outcome occurred in 23.6%, 3.4%, 2.3%, and 0.6% of cohort I patients, respectively. CONCLUSION: Safety profiles were consistent with those known for trastuzumab and chemotherapy; trastuzumab treatment improved outcomes. Our study provides real-world data supporting first-line trastuzumab plus chemotherapy in Chinese patients with HER2-positive mGC. IMPLICATIONS FOR PRACTICE: This prospective, noninterventional registry study aimed to provide safety and effectiveness data for the use of trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive metastatic gastric cancer (mGC) from the real-world clinical setting. Trastuzumab plus first-line chemotherapy was shown to be safe and to improve outcomes when compared with patients treated with chemotherapy alone. Trastuzumab was effective within a range of treatment regimens; subgroup analysis showed that trastuzumab paired most effectively with the XELOX regimen. This study provides real-world clinical safety and effectiveness data supporting the use of trastuzumab in the treatment of Chinese patients with HER2-positive mGC.

Routine-Dose and High-Dose Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation: the Randomized, Phase II, INCREASE Trial.

PURPOSE: Our primary purpose is to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in patients with non-small cell lung cancer (NSCLC) harboring 21-L858R mutation. PATIENTS AND METHODS: Patients with treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 2:1) NSCLC were enrolled. Patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125 mg, thrice daily; L858R-RD) or high-dose icotinib (250 mg, thrice daily; L858R-HD), whereas patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS), assessed by an independent review committee. RESULTS: From May 2015 to November 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD; and 77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del-RD group (12.9 months and 12.5 months, respectively) and was significantly longer than that in L858R-RD group [12.9 months vs. 9.2 months, hazard ratio (HR): 0.75; 95% confidence interval (CI), 0.53-1.05]. A longer but statistically nonsignificant mPFS was observed between 19-Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI, 0.57-1.13). A higher objective response rate (ORR) was observed in L858R-HD group compared with L858R-RD group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups. CONCLUSIONS: High-dose icotinib improved mPFS and ORR in patients with NSCLC harboring 21-L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population.

WBSCR22 Competes with Long Non-coding RNA Linc00346 for miR-509-5p Binding Site to Regulate Cancer Stem Cell Phenotypes of Colorectal Cancer.

Various Long non-coding RNAs (lncRNAs) and MicroRNAs (miRNAs) have been demonstrated to be involved in colorectal cancer stem cells (CSCs). WBSCR22 is a key gene we previously found that functions in colorectal cancer (CRC). This paper aims to investigate the effects of WBSCR22 and its corresponding miRNA and lncRNA in CRC. The expression of WBSCR22 was detected by Western blot and qRT-PCR analysis. Tumor sphere formation assays, CCK-8 analysis, and Transwell assays were applied to examine the colorectal cancer stem cell properties. Luciferase assay and biotin RNA pulldown assay were used to detect the interaction between miR-509-5p and WBSCR22/Linc00346. WBSCR22 is highly expressed in CRC and correlates with poor prognosis. Knockdown of WBSCR22 decreased the sphere-forming capacities, cell proliferation, and invasion abilities. WBSCR22 was negatively regulated by miR-509-5p. Linc00346 promoted the expression of WBSCR22 by adsorbing miR-509-5p. The Linc00346/miR-509-5p/WBSCR22 signal axis regulated the characteristics of colon cancer stem cells. Linc00346 regulated the expression of WBSCR22 by binding to miR-509-5p, thereby monitoring the characteristics of colorectal cancer stem cells. Thus, WBSCR22, Linc00346, and miR-509-5p might be utilized as potential targets for clinical diagnosis and treatment of CRC.

Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: a systematic review and meta-analysis.

The efficacy and safety of direct oral anticoagulants (DOACs) versus low-molecular-weight heparin (LMWH) are still debated in the treatment of patients with cancer, and the optimal duration of therapy remains uncertain. Electronic databases (PubMed, Embase, and Cochrane Library) were searched to retrieve studies on the efficacy and safety of DOACs versus LMWH in treating patients with cancer from January 1980 to October 2018. The primary efficacy and safety endpoints were recurrent venous thromboembolism (VTE) and major bleeding. Our study included two randomized controlled trials (RCTs) and nine observational studies, together comprising 4509 patients with cancer. The pooled estimates indicated that DOACs led to a modest reduction recurrent VTE in the RCTs [RR: 0.63, 95% confidence interval (CI), 0.42-0.96, P = 0.03] and in the observational studies (RR: 0.74, 95% CI, 0.58-0.93, P = 0.011), without increasing the risk of major bleeding for observational studies (P = 0.805), but increased for RCTs (P = 0.017). The same trends were observed in the rivaroxaban subgroup. Moreover, subgroup analyses according to the treatment duration indicated that DOACs significantly reduced the incidence of recurrent VTE (P = 0.006 at 6 months; P < 0.001 at 12 months) without significant differences in major bleeding compared with LMWH at 6 or 12 months. Patients with cancer who received DOACs exhibited a significant reduction in recurrent VTE with no increased risk of major bleeding compared with LMWH. DOACs may be an alternative choice for long-term anticoagulant therapy in patients with cancer.

miR-655-3p inhibits cell migration and invasion by targeting pituitary tumor-transforming 1 in non-small cell lung cancer.

miR-655-3p functions as a tumor suppressor in tumor metastases; however, its role and mechanism in regulating cell migration and invasion of non-small cell lung cancer (NSCLC) remain unclear. Here, we found that miR-655-3p expression was markedly decreased in the NSCLC cell lines A549, NCI-H1650, PC14/b, NCI-H1299, and HPAEpiC compared to levels observed in normal human lung fibroblasts. miR-655-3p overexpression significantly inhibited migration and invasion of A549 and PC14/b cells, and pituitary tumor-transforming 1 (PTTG1) expression was up-regulated in the NSCLC cells. Luciferase reporter assays indicated that PTTG1 was a direct target of miR-655-3p. Additionally, PTTG1 overexpression alleviated the inhibitory effect of miR-655-3p on migration and invasion abilities in A549 and PC14/b cells. In conclusion, miR-655-3p inhibits NSCLC migration and invasion by targeting PTTG1, suggesting that miR-655-3p may serve as a therapeutic target to provide a new approach for the clinical treatment of NSCLC.

Differentiation antagonizing non-protein coding RNA modulates the proliferation, migration, and angiogenesis of glioma cells by targeting the miR-216a/LGR5 axis and the PI3K/AKT signaling pathway.

Purpose: DANCR plays an important role in various types of cancer. However, its role in gliomas remains unclear. In the present study, we aimed to investigate the mechanism underlying the role of DANCR in gliomas. Methods: DANCR expression was measured by qRT-PCR, and expression of LGR5, PI3K, AKT, and phosphorylated AKT (p-AKT) was detected by western blotting. The combination of miR-216a and DANCR was quantified by Luciferase reporter assays. Proliferation, apoptosis and cell cycle, migration and invasion, and angiogenesis of glioma cells were measured by MTT, flow cytometry, Transwell, and Tube formation assays, respectively. Results: DANCR expression was significantly higher in glioma cells than in normal human astrocytes. Silencing of DANCR inhibited proliferation, migration, invasion, and angiogenesis of glioma cells, promoted apoptosis, blocked the cell cycle at the G1/S transition, and reduced LGR5, PI3K, and p-AKT expression. We identified miR-216a as a direct target of DANCR. Silencing of DANCR in glioma cells increased miR-216a expression. Further, miR-216a suppression increased proliferation, migration, invasion, and angiogenesis and inhibited apoptosis of glioma cells transfected with DANCR-targeting siRNA. In addition, miR-216a suppression compromised inhibition of the G1/S transition caused by DANCR silencing. Furthermore, suppression of miR-216a increased accumulation of LGR5, PI3K, AKT, and p-AKT in glioma cells transfected with DANCR-targeting siRNA. Conclusion: DANCR modulates growth and metastasis by targeting the miR-216a/LGR5 axis and PI3K/AKT signaling pathway.

Natural killer cells inhibit oxaliplatin-resistant colorectal cancer by repressing WBSCR22 via upregulating microRNA-146b-5p.

Natural killer (NK) cells have exhibited promising efficacy in inhibiting cancer growth. We aimed to explorer the effect of NK cells on oxaliplatin-resistant colorectal cancer and the underlying molecular mechanism. Oxaliplatin-resistant colorectal cancer cell lines were co-cultured with NK cells to evaluate the effect on viability, proliferation, migration and invasion in vitro. Oxaliplatin-resistant colorectal cancer cells were also co-injected with NK cells into mice to establish xenograft tumor model, to assess the in vivo effect of NK cells on tumorigenesis of the oxaliplatin-resistant colorectal cancer cells. Expression of WBSCR22 gene was assessed in the oxaliplatin-resistant colorectal cancer cells following NK cell treatment to elucidate the mechanism. NK cell treatment significantly reduces growth of oxaliplatin-resistant colorectal cancer cells both in vitro and in vivo, as well as reduced WBSCR22 expression. MicroRNAs potentially targeting WBSCR22 were analyzed, and microRNA-146b-5p was found to be significantly upregulated following NK cell treatment. MicroRNA-146b-5p directly targeted WBSCR22 mRNA 3'-UTR to inhibit its expression, which was required for NK cell-induced inhibition of oxaliplatin-resistant colorectal cancer cell lines. NK cells inhibit oxaliplatin-resistant colorectal cancer by repressing WBSCR22 via upregulating microRNA-146b-5p, both of which could serve as candidates for targeted therapy against oxaliplatin-resistant colorectal cancer.

Combination of cytokine-induced killer and dendritic cells pulsed with antigenic α-1,3-galactosyl epitope-enhanced lymphoma cell membrane for effective B-cell lymphoma immunotherapy.

BACKGROUND AIMS: Refractory B-cell lymphomas are difficult to successfully treat with current chemotherapeutic regimens; however, immunotherapy may be an effective form of treatment for these patients. METHODS: Fourteen refractory lymphoma patients (age, 29-74 y) were enrolled in the trial. α-1,3-galactosyl (α-Gal) epitopes were synthesized on lymphoma cell membranes with the use of bovine recombinant α-1,3-galactosyltransferase (α-GT) and neuraminidase to enhance tumor immunogenicity. Subsequent incubation of processed cell membranes with autologous dendritic cells (DCs) in the presence of human serum containing abundant natural anti-α-Gal immunoglobulin G led to the effective phagocytosis of tumor membranes by DCs. The pulsed DCs and autologous cytokine-induced killer cells were then co-cultured to promote maximum cytotoxicity to lymphoma cells and were infused back into the donor lymphoma patients. Therapeutic responses were assessed by clinical observation, laboratory tests and a computed tomography scan at 6 months after treatment. RESULTS: Complete and partial remission occurred in four and three patients, respectively. The disease status remained unchanged in five patients, and disease progression was observed in two patients. No serious side effects or autoimmune diseases were observed in any participants. Serum lactate dehydrogenase and ß2-macroglobulin decreased in 11 and 14 patients, respectively. All patients showed robust systemic cytotoxicity in response to tumor lysate as measured by interferon-γ expression in peripheral blood mononuclear cells after treatment (P < 0.001). The number of peripheral immune effector cells (CD3(+)/CD4(+), CD8(+)/CD28(+) and CD16(+)/CD56(+) cells) increased significantly (P < 0.05) 3 months after treatment. CONCLUSIONS: Lymphoma cell-specific α-Gal immunotherapy is safe, effective and has great potential for the treatment of refractory B-cell lymphoma.