Immunomodulatory effects of metronomic vinorelbine (mVRL), with or without metronomic capecitabine (mCAPE), in hormone receptor positive (HR+)/HER2-negative metastatic breast cancer (MBC) patients: final results of the exploratory phase 2 Victor-5 study

Abstract

Tregs are able of suppressing tumor-specific effector cells, such as lymphocytes CD8+, CD4+ and Natural Killer cells. Different drugs, especially different schedules of administration, like metronomic chemotherapy (mCHT), seem to be able to increase anticancer immunity, by acting on downregulation of Tregs. Most of the data available regarding the immunomodulating effect of mCHT have been obtained with Cyclophosphamide (CTX). Aim of the present study was to explore the effects of mVRL and mCAPE administration, alone or in combination, on T cells. Observation of 13 metastatic breast cancer patients lasted controlling for 56 days, where Treg frequencies and function, spontaneous anti-tumor T-cell responses were monitored, as well as the clinical outcome. No depletion in Treg absolute numbers, or percentage of T lymphocytes, was observed. Only in 5 patients, a modest and transient depletion of Tregs was observed during the first 14 days of treatment. To better describe the effect on Tregs, we subsequently looked at the variations in Memory, Naïve and Activated Treg subpopulations: we observed a trend in reduction for memory Treg (Treg MEM) and an increase for Treg Naïve (Treg NAIVE) and Treg Activated (Treg ACT) components. We finally analyzed the average trend of Treg in the Treg depleted patients and non-depleted ones, without fiding any significant differences. The trend of the Treg MEM appeared different, showing a reduction during the first 14 days, followed by an increase at the levels before treatment at Day 56 in the group of depleted patients and a progressive substantial reduction in the group of non-depleted patients along the entire course of treatment. Opposed to the data known, treatment with mVRL w/o mCAPE did not show any effect on Tregs.

A phase II study of a doublet metronomic chemotherapy regimen consisting of oral vinorelbine and capecitabine in Chinese women with HER2‐negative metastatic breast cancer

“…Metronomic chemotherapy is an alternative strategy to conventional chemotherapy, which involves administering low doses of chemotherapeutic drugs at frequent intervals, over an extended period of time, without prolonged treatment interruptions 21,22 . This approach is thought to offer several benefits, including antiangiogenic effects, immune modulation and reduced toxicity 23–25 . The detailed mechanisms underlying the antitumor effects of metronomic chemotherapy remain incompletely elucidated.…”

“… 21 , 22 This approach is thought to offer several benefits, including antiangiogenic effects, immune modulation and reduced toxicity. 23 , 24 , 25 The detailed mechanisms underlying the antitumor effects of metronomic chemotherapy remain incompletely elucidated. Possible mechanisms may involve the inhibition of tumor angiogenesis, an induction of tumor dormancy, and the modulation of immune responses.…”

Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation

“…Further confirmations in the clinical setting are urgently needed through randomized trials to assess the role of mCHT in the treatment’s algorithm of TNBC patients. Additionally, even though these data are limited to the TNBC model, inhibition of angiogenesis and block of migration should represent relevant endpoints to be assessed in different subtypes of breast cancer, i.e., HR+ after cell-cycle inhibitors (CDK 4/6) or in those tumors characterized by the loss of endocrine-sensitivity ( 70 ).…”