Personalized therapy for metastatic melanoma: could timing be everything?

Abstract

There is ample evidence that immune-related processes in humans are under temporal regulation. The circadian variation of humoral and cellular immunity is well documented and appears to be hormonally modulated via the hypothalamic-pituitary-adrenal axis. In advanced melanoma, it has recently been demonstrated that systemic immunity is repolarized toward a global state of chronic inflammation (Th2 dominance) and appears to be governed by infradian biorhythms of cytokines and immune cell subsets, which extend beyond the 24-h circadian variability reported in healthy volunteers. It is suggested that synchronizing administration of lymphodepleting chemotherapy (temozolomide) with these endogenous (individualized) immune dynamics (biorhythms) in patients with advanced/metastatic melanoma improves clinical outcomes compared with temozolomide used in a conventional 'random delivery' fashion.

Figure 1

Example of infradian biorhythms of selected cytokines (A) and immune cells (B) in a patient with metastatic melanoma.

Figure 2. Clustering of immunological profiles for prediction of optimal time of chemotherapy delivery in a patient with metastatic melanoma

Bottom panel shows extrapolated relative concentration of selected cytokines; red line shows the summary biorhythm resulting from clustering of immune variables.