PMID- 30756132 OWN - NLM STAT- MEDLINE DCOM- 20190522 LR - 20240426 IS - 1432-0851 (Electronic) IS - 0340-7004 (Print) IS - 0340-7004 (Linking) VI - 68 IP - 5 DP - 2019 May TI - 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. PG - 787-798 LID - 10.1007/s00262-019-02313-z [doi] 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. FAU - Werter, Inge M AU - Werter IM AUID- ORCID: 0000-0002-4411-0450 AD - Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centre, VU University Medical Centre, Vrije University, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. i.werter@vumc.nl. FAU - Huijts, Charlotte M AU - Huijts CM AD - Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centre, VU University Medical Centre, Vrije University, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. FAU - Lougheed, Sinead M AU - Lougheed SM AD - Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centre, VU University Medical Centre, Vrije University, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. FAU - Hamberg, Paul AU - Hamberg P AD - Department of Medical Oncology, Franciscus Gasthuis and Vlietland, Rotterdam, The Netherlands. FAU - Polee, Marco B AU - Polee MB AD - Department of Medical Oncology, Medical Center Leeuwarden, Leeuwarden, The Netherlands. FAU - Tascilar, Metin AU - Tascilar M AD - Department of Medical Oncology, Isala Clinics, Zwolle, The Netherlands. FAU - Los, Maartje AU - Los M AD - Department of Medical Oncology, Saint Antonius Hospital, Nieuwegein, The Netherlands. FAU - Haanen, John B A G AU - Haanen JBAG AD - Department of Medical Oncology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. FAU - Helgason, Helgi H AU - Helgason HH AD - Department of Medical Oncology, Haaglanden Medical Centre, The Hague, The Netherlands. FAU - Verheul, Henk M AU - Verheul HM AD - Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centre, VU University Medical Centre, Vrije University, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. FAU - de Gruijl, Tanja D AU - de Gruijl TD AD - Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centre, VU University Medical Centre, Vrije University, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. FAU - van der Vliet, Hans J AU - van der Vliet HJ AD - Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centre, VU University Medical Centre, Vrije University, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. jj.vandervliet@vumc.nl. CN - Dutch WIN-O Consortium LA - eng GR - VU 2011-5144/KWF Kankerbestrijding (NL)/ GR - ./Novartis Oncology Netherlands/ PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study DEP - 20190211 PL - Germany TA - Cancer Immunol Immunother JT - Cancer immunology, immunotherapy : CII JID - 8605732 RN - 0 (Immunosuppressive Agents) RN - 8N3DW7272P (Cyclophosphamide) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Aged MH - Carcinoma, Renal Cell/*drug therapy/mortality MH - Cell Proliferation MH - Cyclophosphamide/*therapeutic use MH - Everolimus/*therapeutic use MH - Female MH - Follow-Up Studies MH - Humans MH - Immunosuppressive Agents/*therapeutic use MH - Kidney Neoplasms/*drug therapy/mortality MH - Male MH - Middle Aged MH - Survival Analysis MH - T-Lymphocytes, Regulatory/*immunology MH - TOR Serine-Threonine Kinases/metabolism MH - Treatment Outcome PMC - PMC11028263 OTO - NOTNLM OT - Cyclophosphamide OT - Everolimus OT - Tregs OT - mRCC OT - mTOR COIS- The authors declare that they have no competing interests. EDAT- 2019/02/14 06:00 MHDA- 2019/05/23 06:00 PMCR- 2019/02/11 CRDT- 2019/02/14 06:00 PHST- 2018/09/22 00:00 [received] PHST- 2019/02/02 00:00 [accepted] PHST- 2019/02/14 06:00 [pubmed] PHST- 2019/05/23 06:00 [medline] PHST- 2019/02/14 06:00 [entrez] PHST- 2019/02/11 00:00 [pmc-release] AID - 10.1007/s00262-019-02313-z [pii] AID - 2313 [pii] AID - 10.1007/s00262-019-02313-z [doi] PST - ppublish SO - Cancer Immunol Immunother. 2019 May;68(5):787-798. doi: 10.1007/s00262-019-02313-z. Epub 2019 Feb 11.