Efficacy, safety and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms: a multiple-center phase Ib trial.
Toripalimab 在复发或转移性神经内分泌肿瘤患者中的疗效、安全性和生物标志物: 一项多中心 Ib 期试验。
- 作者列表："Lu M","Zhang P","Zhang Y","Li Z","Gong JF","Li J","Li J","Li Y","Zhang X","Lu Z","Wang X","Zhou J","Peng Z","Wang W","Feng H","Wu H","Yao S","Shen L
PURPOSE:Patients with recurrent or metastatic neuroendocrine neoplasms (NENs) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat 2nd line metastatic melanoma in China in 2018. EXPERIMENTAL DESIGN:The multiple-center phase Ib trial enrolled patients with NENs (Ki-67≥10%) after failures of 1st line therapy to received 3 mg/kg toripalimab once every two weeks. The primary objective was objective response rate (ORR) and safety. PD-L1 expression and whole exome sequencing were performed on tumor biopsies. Secondary objectives included duration of response (DOR), disease control rate (DCR), progression free survival and overall survival. RESULTS:Of 40 patients included from April 2017 to December 2018, 8 partial responses and 6 stable diseases were observed, for a 20% ORR and a 35% DCR. The median DOR was 15.2 months. Patients with PD-L1 expression (≥10%) or high tumor mutational burden (TMB) had better ORR than PD-L1 <10% (50.0% vs 10.7%, p=0.019) and TMB low patients (75.0% vs 16.1%, p=0.03). 3/8 (37.5%) responders harbored ARID1A mutations while only 1/27 non-responder was mutated (p=0.03). Of note, 1 exceptional responder with TMB-L, MSS and PD-L1 negative had multiple genomic arrangements with high prediction score for neoantigens. CONCLUSIONS:Toripalimab had antitumor activity and safety in treating recurrent or metastatic NENs. Patients with positive PD-L1 expression, TMB-H (top 10%) and/or MSI-H might preferentially benefit from the treatment. The genomic mutation of ARID1A and high genomic rearrangements might be correlated with clinical benefit.
目的: 复发或转移性神经内分泌肿瘤 (NENs) 患者预后差，治疗选择少。Toripalimab 是一种针对人 PD-1 受体特异性的人源化 IgG4 抗体，2018年在中国首次被批准用于治疗第2 线转移性黑色素瘤。 实验设计: 多中心 Ib 期试验入组了 10% 线治疗失败后的 NENs (Ki-67 ≥ 第1) 患者，每两周接受一次 3 mg/kg toripalimab。主要目标是客观缓解率 (ORR) 和安全性。对肿瘤活检进行 PD-L1 表达和全外显子组测序。次要目标包括缓解时间 (DOR) 、疾病控制率 (DCR) 、无进展生存期和总生存期。 结果: 在 2017年4月至 2018年12月纳入的 40 例患者中，观察到 8 例部分缓解和 6 例疾病稳定，ORR 为 20%，DCR 为 35%。中位 DOR 为 15.2 个月。PD-L1 表达 (≥ 10%) 或高肿瘤突变负荷 (TMB) 的患者 ORR 优于 PD-L1
METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.
METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.