title: 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.
authors.affiliation: Division of Translational Immunology, Tumor Immunology Program, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), INF 460, 69120, Heidelberg, Germany.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Ge
authors.forename: Christoph
authors.initials: C
authors.lastname: Domschke
authors.forename: Natalija
authors.initials: N
authors.lastname: Stoiber
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Joerg
authors.initials: J
authors.lastname: Heil
authors.forename: Joachim
authors.initials: J
authors.lastname: Rom
authors.forename: Maria
authors.initials: M
authors.lastname: Blumenstein
authors.forename: Janina
authors.initials: J
authors.lastname: Thum
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.forename: Florian
authors.initials: F
authors.lastname: Schuetz
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D020298:U937 Cells
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007371:Interferon-gamma; D003520:Cyclophosphamide