Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome

Abstract

Severe immune suppression is frequent in late-stage tumor patients and promotes tumor immune evasion and subsequent tumor progression. Regulatory T cells (Treg) are major suppressors of anti-tumor immune responses. Therefore, targeting of Treg has become a key goal of anti-tumor therapy. Several preclinical and clinical observations suggest that Treg can be depleted by cyclophosphamide. Over a period of 3 months, we investigated the effect of metronomic low-dose cyclophosphamide on Treg numbers, suppressive capacity and proliferation on endogenous anti-tumor T-cell responses and on their correlation to clinical outcome in 12 patients with treatment-refractory metastasized breast cancer who received single-agent 50 mg cyclophosphamide p.o. daily. Cyclophosphamide treatment initially caused a significant reduction in circulating Treg by more than 40% (P = 0.002). However, Treg numbers completely recovered during the treatment due to increased proliferative activity and maintained their suppressive capacity. Treg depletion coincided with a strong increase in breast tumor-reactive T cells (P = 0.03) that remained at high levels during the whole period. Numbers of tumor-reactive T cells but not of Treg correlated with disease stabilization (P = 0.03) and overall survival (P = 0.027). We conclude that metronomic low-dose cyclophosphamide only transiently reduces Treg but induces stable tumor-specific T-cell responses, which correlate with improved clinical outcome in advanced-stage breast cancer patients.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…41,77 A prolonged and more effective Treg inhibition was achieved by metronomic CTX regimens in patients with advanced solid tumors 6 or with metastatic breast cancer. 78 Moreover, metronomic temozolomide, an analog of dacarbazine, reduced the number and the suppressive function of circulating Tregs in rats bearing glioma, although it did not restrain tumor growth. 79 The role of CTX on MDSCs is more controversial.…”

Regulatory T cells in cancer immunotherapy

“…Administration of high-dose cyclophosphamide severely affects all T cells. However, when used at low doses over a long term, the drug has been shown to selectively reduce highly proliferating Treg cells including those in the tumor tissues, and enhance anti-tumor immune responses in humans and rodents [73][74][75][76]. Furthermore, an increasing number of studies have shown the potentials and efficacy of low-dose metronomic cyclophosphamide in combination with other immunotherapeutic agents [77,78].…”

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

“…The previously mentioned clinical studies by Ghiringhelli, et al . 30 and Ge, at al ., 37 also described an increase in effector T cells upon mCTX treatment. In animal models skewing towards a Th1 profile with increased type I interferons and IL-2 upon mCTX treatment was observed, 40,41 which could correspond to the increase in IFNγ+ CD4 and CD8 T cells observed in this study.…”

“…Conflicting results have been published about the effect of mCTX on the suppressive capacity of Tregs; in metastasized breast cancer patients 50 mg cyclophosphamide daily for three months resulted in an initial Treg reduction but a preservation of their suppressive function. 37 Another study in end stage cancer patients treated with 50 mg cyclophosphamide twice daily, one week on and one week off for one month, also found a selective reduction of Tregs, but also a suppression of their inhibitory functions. 30 Since we observed a downregulation of CTLA4 in aTregs, but an upregulation in nTregs, these inconsistent results could be explained by a subset dependent effect of mCTX.…”