Aberrant vascular network is a hallmark of cancer. However, the role of vascular endothelial cells (VECs)-expressing PD-L1 in tumor immune microenvironment and antiangiogenic therapy remains unclear. In this study, we used the specimens of cancer patients for immunohistochemical staining to observe the number of PD-L1+ CD34+ VECs and infiltrated immune cells inside tumor specimens. Immunofluorescence staining and flow cytometry were performed to observe the infiltration of CD8+ T cells and FoxP3+ T cells in tumor tissues. Here, we found that PD-L1 expression on VECs determined CD8+ T cells’, FoxP3+ T cells’ infiltration, and the prognosis of patients with lung adenocarcinoma. Anlotinib downregulated PD-L1 expression on VECs through the inactivation of AKT pathway, thereby improving the ratio of CD8/FoxP3 inside tumor and remolding the immune microenvironment. In conclusion, our results demonstrate that PD-L1 high expression on VECs inhibits the infiltration of CD8+ T cells, whereas promotes the aggregation of FoxP3+ T cells into tumor tissues, thus becoming an “immunosuppressive barrier”. Anlotinib can ameliorate the immuno-microenvironment by downregulating PD-L1 expression on VECs to inhibit tumor growth.

/pdf/anlotinib-alters-tumor-immune-microenvironment-by-5g8uur5zwm.pdf

anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells.

Angiogenesis has an essential role in tumor growth and metastasis, and blocking this pathway has been a successfully utilized strategy in the clinical treatment of cancer. Anlotinib (AL3818) is a novel oral receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 and 3, fibroblast growth factor 1-4, platelet-derived growth factor receptor α and β, c-Kit and Ret. Anlotinib exerts inhibitory effects on tumor growth and angiogenesis and received its first approval as a third-line treatment for refractory advanced non-small-cell lung cancer in May 2018 and its second approval as a second-line treatment for advanced soft-tissue sarcoma in June 2019 in the People's Republic of China. Anlotinib has encouraging efficacy and a manageable and tolerable safety profile in a broad range of malignancies, including medullary thyroid cancer, renal cell cancer, gastric cancer and esophageal squamous cell carcinoma. In the present review, the preclinical and clinical trials of anlotinib were summarized with a focus on safety evaluation and adverse event management.

/pdf/anlotinib-as-a-molecular-targeted-therapy-for-tumors-review-1poueqk1ox.pdf

Anlotinib as a molecular targeted therapy for tumors (Review)

The sites of targeted therapy are limited and need to be expanded. The FGF-FGFR signalling plays pivotal roles in the oncogenic process, and FGF/FGFR inhibitors are a promising method to treat FGFR-altered tumours. The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours. While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment. In addition, biomarkers need to be developed to predict the efficacy, and combination with immune checkpoint inhibitors is a promising direction in the future. The article will discuss the FGF-FGFR signalling pathway, the VEGF-VEGFR signalling pathway, the rationale of combining these two signalling pathways and recent small-molecule FGFR/VEGFR inhibitors based on clinical trials.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cpr.13009

Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor derived from bile duct epithelium. Its characteristics include an insidious onset and frequent recurrence or metastasis after surgery. Current chemotherapies and molecular target therapies provide only modest survival benefits to patients with ICC. Anlotinib is a novel multi-target tyrosine kinase inhibitor that has good antitumor effects in a variety of solid tumors. However, there are few studies of anlotinib-associated mechanisms and use as a treatment in ICC. In this study using in vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration and invasion restraint, and cell-cycle arrestment. Anlotinib treatment affected induction of apoptosis and the mesenchymal-epithelial transition. Patient-derived xenograft models generated directly from patients with ICC revealed that anlotinib treatment dramatically hindered in vivo tumor growth. We also examined anlotinib's mechanism of action using transcriptional profiling. We found that anlotinib treatment might mainly inhibit tumor cell proliferation and invasion and promote apoptosis via cell-cycle arrestment by inactivating the VEGF/PI3K/AKT signaling pathway, as evidenced by significantly decreased phosphorylation levels of these kinases. The activation of vascular endothelial growth factor receptor 2 (VEGFR2) can subsequently activate PI3K/AKT signaling. We identified VEGRF2 as the main target of anlotinib. High VEGFR2 expression might serve as a promising indicator when used to predict a favorable therapeutic response. Taken together, these results indicated that anlotinib had excellent antitumor activity in ICC, mainly via inhibiting the phosphorylation level of VEGFR2 and subsequent inactivation of PIK3/AKT signaling. This work provides evidence and a rationale for using anlotinib to treat patients with ICC in the future.

/pdf/anlotinib-suppresses-tumor-progression-via-blocking-the-5bax4h6pxi.pdf

Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma.

Purpose Anlotinib, a newly developed oral small-molecule receptor tyrosine kinase inhibitor (TKI), has been shown to have encouraging activity against sarcoma. The purpose of this study was to retrospectively evaluate the safety and clinical efficacy of chemotherapy combined with anlotinib plus anlotinib maintenance in advanced/metastatic soft tissue sarcoma (STS) patients in a real-world setting in China. Patients and methods We retrospectively collected the medical data of thirty-two patients with advanced/metastatic STS who received chemotherapy combined with anlotinib plus anlotinib maintenance therapy. The objective response rate (ORR) and disease control rate (DCR) were calculated according to the RECIST 1.1 criteria. The progression-free rates (PFRs) at three and six months, the progression-free survival (PFS) time, and adverse events were recorded. Results On the basis of investigator assessments, two patients (6%) achieved CR (complete response) and nine patients (28%) achieved PR (partial response), with an ORR of 34%. Eleven patients (34%) achieved SD (stable disease), and ten patients (31%) achieved PD (progression disease), with a DCR of 69%. The progression-free rates (PFRs) at three and six months were 81% and 69%, respectively. The median PFS time was 8.2 months. The hematologic and non-hematologic toxicities were manageable. The most common grade 3 and 4 adverse events were febrile neutropenia (9%), leukopenia (19%), thrombocytopenia (3%), anemia (6%), anorexia (6%), vomiting (3%), and hypertension (6%). The combination therapy was generally well tolerated. Conclusion Our study suggests that chemotherapy combined with anlotinib plus anlotinib maintenance therapy had good efficacy and resulted in more favorable survival with good tolerance among patients with advanced/metastatic STS.

/pdf/safety-and-efficacy-of-chemotherapy-combined-with-anlotinib-3y76fmxqh2.pdf

Safety and Efficacy of Chemotherapy Combined with Anlotinib Plus Anlotinib Maintenance in Chinese Patients with Advanced/Metastatic Soft Tissue Sarcoma.

BACKGROUND Anlotinib is a tyrosine kinase inhibitor inhibiting angiogenesis. This multicenter, randomized phase II trial aimed to investigate the efficacy and safety of anlotinib in comparison with sunitinib as first-line treatment for patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS Patients with mRCC from 13 clinical centers were randomly assigned in a 2:1 ratio to receive anlotinib (n = 90) or sunitinib (n = 43). Anlotinib was given orally at a dose of 12 mg once daily (2 weeks on/1 week off), and sunitinib was given orally at 50 mg once daily (4 weeks on/2 weeks off). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS The median PFS was similar with anlotinib and sunitinib (17.5 vs. 16.6 months, p > .05). The median OS (30.9 vs. 30.5 months, p > .05), ORR (30.3% vs. 27.9%), and 6-week DCR (97.8% vs. 93.0%) were similar in the two groups. Adverse events (AEs) of grade 3 or 4 were significantly less frequent with anlotinib than with sunitinib (28.9% vs. 55.8%, p < .01), especially in terms of thrombocytopenia and neutropenia. AEs occurring at a lower frequency with anlotinib were hand-foot syndrome, eyelid edema, hair depigmentation, skin yellowing, neutropenia, thrombocytopenia, and anemia. The incidence of serious AEs was lower with anlotinib than with sunitinib. CONCLUSION The clinical efficacy of anlotinib was similar to that of sunitinib as the first-line treatment for mRCC, but with a more favorable safety profile. IMPLICATIONS FOR PRACTICE This study evaluated the efficacy and safety of anlotinib for the first-line treatment of metastatic renal cell carcinoma. Anlotinib, which was developed independently in China, is a new tyrosine kinase inhibitor inhibiting multiple kinases involved in angiogenesis and tumor proliferation. Results indicated that the efficacy of anlotinib is comparable to and the safety is better than that of sunitinib.

Xiu Bao Ren

Papers

Anlotinib Versus Sunitinib as First-Line Treatment for Metastatic Renal Cell Carcinoma: A Randomized Phase II Clinical Trial