title: Depletion of T lymphocytes is correlated with response to temozolomide in melanoma patients.
abstract: Therapeutic strategies to deplete lymphocytes, especially regulatory T cells, in cancer patients have been proposed to increase the benefits of (immuno)chemotherapy. In this study, we explored the influence of temozolomide (TMZ) on different T-cell populations and addressed if the depletion of CD4+T cells would be associated to the clinical benefits of TMZ. Patients were treated with TMZ (150 mg/m2daily, every two weeks on a four-week schedule) until disease progression. Changes in T-lymphocyte subsets were characterized by flow cytometry. All patients enrolled in this study had histologically verified unresectable stage IV melanoma. Objective responses were induced in 12.5% of the patients, while 42.5% of them obtained short-term disease stabilization. The median progression-free survival (PFS) of this patient cohort was 8.7 mo. Lymphopenia (< 0.7 × 109cells/L, grade 2) developed in 71% of the patients after 3 treatment cycles (~100 d). The development of grade 2 lymphopenia after the 3rd cycle of therapy positively correlated with clinical outcome (p = 0.01), and was linked, though non-significantly, to prolonged median PFS (303 vs. 200 d). In addition, significant changes in CD8+T-cell subgroups were observed, notably a shift from naïve T cells toward more differentiated memory T cells. Finally, we demonstrated that specific CD8+T-cell responses against selected tumor associated antigens (TAAs) were enhanced by the administration of TMZ (p = 0.04), while virus-specific T-cell responses were stable. Thus, immunological monitoring in the course of TMZ treatment might become an important tool for clinical guidance in the future.
authors.affiliation: Department of Haematology and Oncology; Center for Cancer Immune Therapy (CCIT); Copenhagen University Hospital at Herlev; Herlev, Denmark.
authors.forename: Trine Zeeberg
authors.initials: TZ
authors.lastname: Iversen
authors.forename: Marie Klinge
authors.initials: MK
authors.lastname: Brimnes
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nikolajsen
authors.forename: Rikke Sick
authors.initials: RS
authors.lastname: Andersen
authors.forename: Sine Reker
authors.initials: SR
authors.lastname: Hadrup
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
authors.forename: Lars
authors.initials: L
authors.lastname: Bastholt
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
keywords: lymphocytes; lymphopenia; metastatic melanoma; regulatory T cells; temozolomide