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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
At the time of writing, the majority of clinical trials of therapies based on dendritic cells are at the Phase I/II. Approximately 90% of these studies are investigating the use of DCs in solid tumors, including gastrointestinal and prostate cancer, and melanoma. Furthermore, 13 of these trials are based on the use of DCs in combination with cytotoxic T lymphocytes. The DCs are induced from peripheral blood and then loaded with antigens and re-infused. This is known as Multiple Target Antigen Stimulating Cell Therapy (MASCT-1). Recently, a Phase I/II trial evaluated the safety and efficacy of combining apatinib (a receptor tyrosine kinase inhibitor) with MASCT-1 therapy in patients with advanced bone and soft tissue sarcoma. The investigators found that patients administered with a PD-1 blockade-activated MASCT in combination with apatinib achieved higher objective response rates than patients treated with the MASCT alone. Furthermore, they found that the use of apatinib did not increase immunotherapy-related toxicity in patients with advanced solid tumors.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Apatinib, a novel vascular endothelial growth factor receptor-2 inhibitor, is an investigational anticancer drug currently undergoing clinical III trials as a potential targeted treatment for metastatic gastric carcinoma, metastatic breast cancer, and advanced hepatocellular carcinoma (Geng and Li 2015; Hu et al. 2014a,b; Li et al. 2013; Tian et al. 2011). The primary metabolic routes of apatinib in humans include E- and Z-cyclopentyl-3-hydroxylation, N-dealkylation, pyridyl-25-N-oxidation, 16-hydroxylation, dioxygenation, and O-glucuronidation after 3-hydroxylation (Li et al. 2010). Nine major metabolites formed in vivo are confirmed by comparison with reference standards. The total recovery of the administered dose is 76.8% within 96 h post-dose, with 69.8% and 7.02% of the administered dose excreted in feces and urine, respectively (Li et al. 2010). Approximately 59.0% of the administered dose is excreted unchanged into feces. Unchanged apatinib is detected in negligible quantities in urine, indicating that systemically available apatinib is extensively metabolized. The major circulating metabolite is the pharmacologically inactive E-3-hydroxy-apatinib-O-glucuronide (M9-2), the steady-state exposure of which is 125% that of apatinib. The steady-state exposures of E-3-hydroxy-apatinib (M1-1), Z-3-hydroxy-apatinib (M1-2), and apatinib-25-N-oxide (M1-6) are 56%, 22%, and 32% of parent drug exposure, respectively. Apatinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, by 2D6, 2C9, and 2E1 (Ding et al. 2013). UGT2B7 is the main enzyme responsible for M9-2 formation. Both UGT1A4 and 2B7 are responsible for the formation of Z-3-hydroxy-apatinib-O-glucuronide (M9-1) (Ding et al. 2013).
The anti-tumor efficiency of low-dose apatinib-based chemotherapy in pretreated HER2-negative breast cancer with brain metastases
Published in Annals of Medicine, 2023
Xuelian Chen, Xue Bai, Xiaofeng Xie, Jiayi Huang, Liping Chen, Lin Song, Xiaofeng Lan, Qiuyi Zhang, Jinfeng Guo, Caiwen Du
Apatinib is an anti-angiogenic TKI targeting VEGFR-2 through selective competition for ATP binding sites [17]. Clinical research on MBC have shown that apatinib monotherapy was effective against both heavily pretreated triple-negative and other subtypes of breast cancer with manageable toxicities [18,19]. Apatinib alone has shown specific CNS activity in some case reports [20,21]. The combination of apatinib and chemotherapy could obtain synergistic effects in cell lines of breast cancer [22]. Herein, we hypothesize that apatinib, as a small-molecule oral TKI, is potential to penetrate across BBB and could be a promising choice for HER2-negative BCBM. In this study, we retrospectively investigated the effectiveness and safety of low-dose apatinib combined with chemotherapy in pretreated HER2-negative BCBM based on real-world data and tried to identify patients who may benefit from this regimen.
Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study
Published in OncoImmunology, 2021
Wencheng Zhang, Cihui Yan, Tian Zhang, Xi Chen, Jie Dong, Jingjing Zhao, Dong Han, Jun Wang, Gang Zhao, Fuliang Cao, Dejun Zhou, Hongjing Jiang, Peng Tang, Lujun Zhao, Zhiyong Yuan, Quanren Wang, Ping Wang, Qingsong Pang
Reactive capillary endothelial proliferation was the most common immune-related adverse event reported in camrelizumab monotherapy (75–79%).12,17 In our recent phase 1b study of camrelizumab combined with radiotherapy in locally advanced ESCC, it was observed in 89% (17/19) patients (79% [15/19] grade 1, 10% [2/19] grade 2).15 Apatinib independently developed in China is an oral small-molecule tyrosine kinase inhibitor that selectively binds to and inhibits vascular endothelial growth factor receptor 2, with a decrease in VEGF-mediated endothelial cell migration, proliferation, and tumor microvascular density. Apatinib has been approved for use in gastric adenocarcinoma or gastroesophageal junction in China.38 The latest phase 2 study of camrelizumab plus apatinib and chemotherapy in advanced ESCC reported the incidence of reactive capillary hemangiomas at 60% (18/30) and high objective response rate at 80%.39 In the present study, we added apatinib during the maintenance treatment of camrelizumab originally to decrease the occurrence of reactive capillary endothelial proliferation. The result showed reactive capillary endothelial proliferation occurred in a much lower frequency (50%, [10/20]), and was all in grade 1 without special treatment. These results suggest that combining camrelizumab with apatinib could inhibit reactive cutaneous capillary endothelial proliferation. We also found noninfectious pneumonia and dermatitis occurred in three (15%) patients each. However, it was hard to determine whether these resulted from activated immune response or radiotherapy.
A bivalent cyclic RGD–siRNA conjugate enhances the antitumor effect of apatinib via co-inhibiting VEGFR2 in non-small cell lung cancer xenografts
Published in Drug Delivery, 2021
Lumin Liao, Bohong Cen, Guoxian Li, Yuanyi Wei, Zhen Wang, Wen Huang, Shuai He, Yawei Yuan, Aimin Ji
Apatinib, also known as YN968D1, is a novel oral tyrosine kinase inhibitor (TKI) that selectively inhibits VEGFR2, thus exerting an antiangiogenic effect and inhibiting tumor proliferation including NSCLC (Tian et al., 2011; Fan et al., 2020). Especially, apatinib has showed several notable characteristics, such as promoting tumor size shrinkage, inducing tumor regression and facilitating metastasis confinement, which are rarely found in other anti-angiogenic drugs. However, apatinib is also faced with the dilemma of short term of response, drug resistance and adverse effects including hypertension, proteinuria and hand-foot syndrome when it is used for a long time (Yang et al., 2020). Therefore, it is necessary to develop new targeted therapy to inhibit VEGFR2 in order to obtain better anti-tumor activity, fewer side effects and lower drug resistance.