Targeting Angiogenesis in the Era of Biliary Tract Cancer Immunotherapy: Biological Rationale, Clinical Implications, and Future Research Avenues.

Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone.

Corrigendum: Variations in circulating levels of angiopoietin-2 over time are predictive of ramucirumab-paclitaxel therapy outcome in advanced gastric cancer: results of prospective study.

[This corrects the article DOI: 10.3389/fonc.2022.862116.].

Durvalumab in advanced cholangiocarcinoma: is someone knocking down the door?

Following the practice-changing results observed in several hematological and solid tumors, immunotherapy with immune checkpoint inhibitors (ICIs) has been tested in cholangiocarcinoma (CCA) patients. However, ICI monotherapy has had disappointing results in CCA, and phase I-III clinical trials have assessed whether combinatorial strategies including immunotherapy plus other anticancer agents may have a synergistic activity. The TOPAZ-1 trial has recently highlighted improved survival in CCA patients receiving first-line durvalumab plus gemcitabine-cisplatin compared with gemcitabine plus cisplatin alone, and several guidelines consider adding durvalumab to the reference doublet as standard of care. This article provides an overview of durvalumab pharmacology, safety and efficacy in CCA, highlighting current and future research directions in this setting.

Several treatments have been recently tested for cholangiocarcinoma patients. Among these, interesting results have been reported for immunotherapy with durvalumab, and the combination of immunotherapy plus chemotherapy represents a novel and important option in this setting.

Variations in Circulating Levels of Angiopoietin-2 Over Time Are Predictive of Ramucirumab-Paclitaxel Therapy Outcome in Advanced Gastric Cancer: Results of Prospective Study.

The combination of paclitaxel and ramucirumab is the second-line therapy of choice in the treatment of advanced gastric cancer. To date, no biomarkers are available in gastric cancer to predict the outcome of antiangiogenic therapy. The present prospective study included 35 patients undergoing second-line therapy with ramucirumab and paclitaxel. Serum samples were systematically collected from the beginning of therapy and at each cycle until disease progression. Multiplex analysis of a panel of angiogenic factors identified markers for which the changes at defined time intervals were significantly different in patients with progression-free survival ≤3 (Rapid Progression Group) compared to those with progression-free survival >3 (Control Disease Group). Comparative analysis revealed significantly different results in the two groups of patients for VEGFC and Angiopoietin-2, both involved in angiogenesis and lymphangiogenesis. VEGFC increased in the progressive-disease group, while it decreased in the control-disease group. This decrease persisted beyond the third cycle, and it was statistically significant compared to the basal level in patients with longer progression-free survival. Angiopoietin-2 decreased significantly after 2 months of therapy. At progression time, there was a significant increase in VEGFC and Angiopoietin-2, suggesting the activation pathways counteracting the blockade of VEGFR2 by ramucirumab. Overall results showed that a greater change in VEGFC and Angiopoietin-2 levels measured at the beginning of the third cycle of therapy corresponded to a lower risk of progression and thus to longer progression-free survival.

Molecular mechanisms of synergistic action of Ramucirumab and Paclitaxel in Gastric Cancers cell lines.

Ramucirumab is approved both as monotherapy and in combination with Paclitaxel for advanced gastric cancer in patients with disease progression after chemotherapy. In tumor cells, the VEGFA-VEGFR2 binding activates autocrine survival and migration signaling in angiogenesis independent manner. The present in vitro study investigated the effects of single and combined treatments with Ramucirumab and Paclitaxel on cell growth and migration highlighting the mechanisms underlying the interaction between the two drugs in gastric cancer cells. Cell growth and motility were investigated in human gastric cancer cell lines characterized by different tumorigenicity. The inhibitory effect on cell growth exerted by both drugs was potentiated by their combination and was synergistic. Ramucirumab was able to enhance the inhibitory effect exerted by Paclitaxel on cell cycle progression. A synergistic action was also observed in the expression of proteins crucial for cell motility, microtubule organization and epithelial-mesenchymal transition. Furthermore, synergistic inhibition of VEGFR2 expression was obtained by the drug combination. These findings highlighted the importance of the combined treatment to strongly inhibit all the main molecules of both PI3K/Akt/mTOR and MAPK pathways thus preventing possible reactivations due to cross-talk phenomena. The combined treatment with Ramucirumab seems to be a promising option to overcome the Paclitaxel resistance.