[Frontiers in Bioscience E4, 958-975, January 1, 2012]

Fluctuation of systemic immunity in melanoma and implications for timing of therapy

Alexey A. Leontovich2, Roxana S. Dronca3, Vera J. Suman2, Martin L.Ashdown4, Wendy K. Nevala1, Michael A. Thompson1, Andrew Robinson5, Lisa A. Kottschade3, Judith S. Kaur3, Robert R. McWilliams3, Leonid V. Ivanov6, Gary A. Croghan3, Svetomir N. Markovic1,3

1Department of Hematology, Mayo Clinic, Rochester, MN, USA, 2Department of Health Science research, Mayo Clinic, Rochester, MN, USA, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA, 3Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA, 4Department of Medicine University of Melbourne Melbourne, Victoria, Australia, 5Department of Mathematics and Statistics University of Melbourne Parkville, Melbourne, Victoria, Australia , 6 College and Alumni Relations, Grinnell College, IA, USA


1. Abstract
2. Introduction
3. Materials and methods
3.1. Patient population and study design
3.2. Immunological studies
3.2.1. Peripheral blood mononuclear cell (PBMC) immunophenotyping for immune cell subsets.
3.2.2. Plasma cytokine profiling.
3.3. Statistical considerations
3.4. Data analysis
4. Results
4.1. Patient characteristics and clinical outcomes
4.2. Dynamic changes of systemic immunity in metastatic melanoma
4.3. Identification of immunologically favorable time point in the immune response cycle (rhythm) for chemotherapy administration based on fluctuating systemic immune biomarkers
4.4. Full data integration and correlation with clinical outcome (clustering analysis)
4.5. The simulation model
5. Discussion
6. Acknowledgments
7. References


Evidence suggests that immunological response in chronic inflammation is dynamic, oscillating between active immunity and tolerance. We hypothesized that a similar dynamic exists in melanoma and administration of therapy during a unique phase of such oscillation could impact clinical outcome. Patients with metastatic melanoma eligible to undergo temozolomide underwent serial measurements of C-reactive protein (CRP) and immune biomarkers every 2-3 days for 2 weeks before starting therapy. Treatment was initiated prior to the estimated next CRP peak, or on day 14 post-registration if a peak was not identified. Time profiles of measured biomarkers were analyzed by fitting serially measured data points to 9 mathematical functions and were correlated to time of therapy and outcome. Data suggested that metastatic melanoma patients exhibit a dynamic immune response. The fluctuation of several biomarkers fitted cosine functions with periods which were multiples of 3-4 days. Chemotherapy delivery during a unique phase of this cycle seemed to correlate with improved response. Individualized conventional chemotherapy delivery by synchronizing treatment with pre-existing patient-specific biorhythms may improve clinical outcomes in metastatic melanoma.