Depletion of T lymphocytes is correlated with response to temozolomide in melanoma patients

Trine Zeeberg Iversen, Marie Klinge Brimnes, Kirsten Nikolajsen, Rikke Sick Andersen, Sine Reker Hadrup, Mads Hald Andersen, Lars Bastholt, Inge Marie Svane

Research output: Contribution to journalJournal articleResearchpeer-review

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/m(2) daily, every two weeks on a 4-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 x 10(9) cells/L, grade 2) developed in 71% of the patients after 3 treatment cycles (similar to 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 naive 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.
Original languageEnglish
Article numbere23288
JournalOncoImmunology
Volume2
Issue number2
ISSN2162-4011
DOIs
Publication statusPublished - 2013
Externally publishedYes

Keywords

  • Immunology and Allergy
  • Oncology
  • Immunology
  • Lymphocytes
  • Lymphopenia
  • Metastatic melanoma
  • Regulatory T cells
  • Temozolomide
  • temozolomide
  • tumor antigen
  • adult
  • aged
  • article
  • cancer immunology
  • cancer staging
  • cancer survival
  • CD8+ T lymphocyte
  • cell assay
  • clinical article
  • clinical effectiveness
  • clinical trial
  • disease severity
  • drug efficacy
  • drug response
  • drug safety
  • drug tolerability
  • female
  • flow cytometry
  • histopathology
  • human
  • human cell
  • immunological monitoring
  • lymphocyte differentiation
  • lymphocyte subpopulation
  • lymphocytopenia
  • male
  • melanoma
  • memory T lymphocyte
  • multiple cycle treatment
  • outcome assessment
  • patient assessment
  • priority journal
  • progression free survival
  • T cell depletion
  • treatment duration
  • Environmental Chemistry
  • Pollution
  • Waste Management and Disposal
  • Materials Chemistry
  • Aliphatic amines
  • Corrosion
  • Hydantoin
  • Quantum
  • Thermodynamic
  • Apparent stability constant
  • Chelation sites
  • Gadolinium complexes
  • Glycolate
  • Indirect photometry
  • Malate
  • Oxalate
  • Essential oil
  • Hydrodistillation
  • Microwave-assisted hydrodistillation
  • Monoterpene hydrocarbons
  • Oxygenated monoterpenes
  • Rosmarinus eriocalyx
  • Dielectric study
  • DSC
  • Nanocomposite
  • Percolation
  • PS/CNPs
  • UV-vis Analysis
  • Aromatic plants
  • Icp-aes
  • Mineral contents
  • Soil
  • The heavy metal
  • Cerium coating
  • Corrosion inhibition
  • Interaction energy
  • Molecular dynamics
  • ONCOLOGY
  • IMMUNOLOGY
  • STAGE-IV MELANOMA
  • METASTATIC MELANOMA
  • PHASE-II
  • PARALLEL DETECTION
  • SUPPRESSOR-CELLS
  • CANCER-PATIENTS
  • MHC MULTIMERS
  • IMMUNOTHERAPY
  • TRIAL
  • INTERLEUKIN-2
  • lymphocytes
  • lymphopenia
  • metastatic melanoma
  • regulatory T cells
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common adult, aged, aged/80 and over, middle age female, male
  • temozolomide TMZ 85622-93-1 antineoplastic-drug dosage
  • tumor associated antigen TAA
  • 02506, Cytology - Animal
  • 02508, Cytology - Human
  • 12502, Pathology - General
  • 12512, Pathology - Therapy
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
  • 18506, Integumentary system - Pathology
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 24003, Neoplasms - Immunology
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 24008, Neoplasms - Therapeutic agents and therapy
  • 24010, Neoplasms - Blood and reticuloendothelial neoplasms
  • 24500, Gerontology
  • 34502, Immunology - General and methods
  • 34508, Immunology - Immunopathology, tissue immunology
  • Clinical Immunology
  • Dermatology
  • Pharmacology
  • lymphopenia Lymphopenia (MeSH) blood and lymphatic disease, immune system disease
  • melanoma Melanoma (MeSH) neoplastic disease, integumentary system disease drug therapy, mortality, pathology
  • cell response
  • clinical benefit
  • clinical guidance
  • Human Medicine, Medical Sciences
  • CD4-positive T cell immune system, blood and lymphatics
  • T lymphocyte immune system, blood and lymphatics
  • flow cytometry laboratory techniques, histology and cytology techniques
  • immunological monitoring clinical techniques, diagnostic techniques

Cite this

Iversen, T. Z., Brimnes, M. K., Nikolajsen, K., Andersen, R. S., Hadrup, S. R., Andersen, M. H., Bastholt, L., & Svane, I. M. (2013). Depletion of T lymphocytes is correlated with response to temozolomide in melanoma patients. OncoImmunology, 2(2), [e23288]. https://doi.org/10.4161/onci.23288