Analysis of the dynamics in the immune system of patients with metastatic melanoma in response to systemic therapy with metastatic melanoma in response to systemic therapy.

Abstract

e19003 Background: Biorhythmic fluctuations of cellular function are well established in human hematopoietic and immune systems. Evidence exists that efficacy and toxicity of anticancer drug therapy may be influenced by immune biorhythms in animal models. Longer periods (circaseptan – 7 days and ifradian – 19-22 days) are poorly studied. A recent publication demonstrated 12-14 days periodicity of the serum level of C- reactive protein (CRP) in HIV patients. The role and mechanism of the circaseptan and ifradian rhythms of immunity in human cancer are unknown. Measurements of peripheral blood oscillations of C-reactive protein (CRP) and other immune biomarkers could be used as a surrogate for the periodicity of the antitumor immune response and be potentially utilized for timed delivery of chemotherapy. Methods: Eleven patients with metastatic melanoma underwent measurements of 27 cytokines and 25 immune cell counts every 2-3 days for 2 weeks. Chemotherapy was initiated at the time of the predicted peak of CRP concentration for the given patient. Results: We constructed time-depended profiles of cytokine concentrations and cell counts and analyzed the dynamic of these variables. We developed an index which characterizes the immuno-activity of each variable at any point in its biorhythm profile. This index correlated with clinical outcome. The PFS for the two patients with the highest index rank was > 2 years, compared to < 5 months for all other patients. The fluctuations of most variables fitted to cosine functions with discrete periods (multiples of 3 days). Administration of therapy relative to the dynamic trend of a cytokine/cell count correlated with PFS. Computer simulation was performed to estimate sensitivity and specificity of data fitting to cosine curve. The analysis confirmed periodical pattern of the described fluctuations. Conclusions: Components of immune homeostasis change in a regular fashion, many of them follow a periodical pattern. This temporal variation correlates with clinical outcome (PFS) and may be utilized for timing of chemotherapy relative to the immune cycle. No significant financial relationships to disclose.