TY - JOUR
T1 - Metronomic cyclophosphamide attenuates mTOR-mediated expansion of regulatory T cells, but does not impact clinical outcome in patients with metastatic renal cell cancer treated with everolimus
AU - Dutch WIN-O Consortium
AU - Werter, Inge M.
AU - Huijts, Charlotte M.
AU - Lougheed, Sinéad. M.
AU - Hamberg, Paul
AU - Polee, Marco B.
AU - Tascilar, Metin
AU - Los, Maartje
AU - Haanen, John B. A. G.
AU - Helgason, Helgi H.
AU - Verheul, Henk M.
AU - de Gruijl, Tanja D.
AU - van der Vliet, Hans J.
N1 - Funding Information: Funding The trial was supported by the Dutch Cancer Society (Grant number: VU 2011–5144) and partly funded by a grant from Novartis Oncology Netherlands. Novartis has had no part in study design, data collection, analysis, interpretation, the writing of the manuscript or the decision to submit for publication. Publisher Copyright: © 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Introduction: Metastatic renal cell cancer (mRCC) patients have a median overall survival (mOS) of approximately 28 months. Until recently, mammalian target of rapamycin (mTOR) inhibition with everolimus was the standard second-line treatment regimen for mRCC patients, improving median progression-free survival (mPFS). Treatment with everolimus supports the expansion of immunosuppressive regulatory T cells (Tregs), which exert a negative effect on antitumor immune responses. In a phase 1 dose-escalation study, we have recently demonstrated that a low dose of 50 mg oral cyclophosphamide once daily can be safely combined with everolimus in mRCC patients and prevents the everolimus-induced increase in Tregs. Materials and methods: In a multicenter phase 2 study, performed in patients with mRCC not amenable to or progressive on a vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor (TKI) containing treatment regimen, we assessed whether the addition of this metronomic dosing schedule of cyclophosphamide to therapy with everolimus could result in an improvement of progression-free survival (PFS) after 4 months of treatment. Results: Though results from this study confirmed that combination treatment effectively lowered circulating levels of Tregs, addition of cyclophosphamide did not improve the PFS rate at 4 months. For this reason, the study was abrogated at the predefined interim analysis. Conclusion: Although the comprehensive immunomonitoring analysis performed in this study provides relevant information for the design of future immunotherapeutic approaches, the addition of metronomic cyclophosphamide to mRCC patients receiving everolimus cannot be recommended.
AB - Introduction: Metastatic renal cell cancer (mRCC) patients have a median overall survival (mOS) of approximately 28 months. Until recently, mammalian target of rapamycin (mTOR) inhibition with everolimus was the standard second-line treatment regimen for mRCC patients, improving median progression-free survival (mPFS). Treatment with everolimus supports the expansion of immunosuppressive regulatory T cells (Tregs), which exert a negative effect on antitumor immune responses. In a phase 1 dose-escalation study, we have recently demonstrated that a low dose of 50 mg oral cyclophosphamide once daily can be safely combined with everolimus in mRCC patients and prevents the everolimus-induced increase in Tregs. Materials and methods: In a multicenter phase 2 study, performed in patients with mRCC not amenable to or progressive on a vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor (TKI) containing treatment regimen, we assessed whether the addition of this metronomic dosing schedule of cyclophosphamide to therapy with everolimus could result in an improvement of progression-free survival (PFS) after 4 months of treatment. Results: Though results from this study confirmed that combination treatment effectively lowered circulating levels of Tregs, addition of cyclophosphamide did not improve the PFS rate at 4 months. For this reason, the study was abrogated at the predefined interim analysis. Conclusion: Although the comprehensive immunomonitoring analysis performed in this study provides relevant information for the design of future immunotherapeutic approaches, the addition of metronomic cyclophosphamide to mRCC patients receiving everolimus cannot be recommended.
KW - Aged
KW - Carcinoma, Renal Cell/drug therapy
KW - Cell Proliferation
KW - Cyclophosphamide
KW - Cyclophosphamide/therapeutic use
KW - Everolimus
KW - Everolimus/therapeutic use
KW - Female
KW - Follow-Up Studies
KW - Humans
KW - Immunosuppressive Agents/therapeutic use
KW - Kidney Neoplasms/drug therapy
KW - Male
KW - Middle Aged
KW - Survival Analysis
KW - T-Lymphocytes, Regulatory/immunology
KW - TOR Serine-Threonine Kinases/metabolism
KW - Treatment Outcome
KW - Tregs
KW - mRCC
KW - mTOR
UR - http://www.scopus.com/inward/record.url?scp=85061505522&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00262-019-02313-z
DO - https://doi.org/10.1007/s00262-019-02313-z
M3 - Article
C2 - 30756132
SN - 0340-7004
VL - 68
SP - 787
EP - 798
JO - Cancer Immunology, Immunotherapy
JF - Cancer Immunology, Immunotherapy
IS - 5
ER -