Research: Mitoxantrone and Progression

Chanvillard C et al. Mitoxantrone induces natural killer cell maturation in patients with secondary progressive multiple sclerosis. PLoS One. 2012;7:e39625. Epub 2012 Jun 29

Mitoxantrone is one of the few drugs approved for the treatment of progressive multiple sclerosis (MS). However, the prolonged use of this potent immunosuppressive agent is limited by the appearance of severe side effects. Apart from its general cytotoxic effect, the mode of action of mitoxantrone on the immune system is poorly understood. 

Thus, to develop safe therapeutic approaches for patients with progressive MS, it is essential to elucidate how mitoxantrone exerts it benefits. Accordingly, we initiated a prospective single-arm open-label study with 19 secondary progressive MS patients. We investigated long-term effects of mitoxantrone on patient peripheral immune subsets using flow cytometry. While we corroborate that mitoxantrone persistently suppresses B cells in vivo, we show for the first time that treatment led to an enrichment of neutrophils and immunomodulatory CD8(low) T cells. Moreover, sustained mitoxantrone applications promoted not only persistent NK cell enrichment but also NK cell maturation. Importantly, this mitoxantrone-induced NK cell maturation was seen only in patients that showed a clinical response to treatment. Our data emphasize the complex immunomodulatory role of mitoxantrone, which may account for its benefit in MS. In particular, these results highlight the contribution of NK cells to mitoxantrone efficacy in progressive MS.

 In my mind it is not clear how mitoxantrone influences progression, unless it inhibits immune activity in progressive MS and indeed this study suggests that is only active in people with some form of altered immune activity and indicates that it affects natural killer cells. This is a type of immune cell that usually gets rid of cancerous cells. What they do in MS is obscure but it seems that dacluzimab, which is an anti CD25-specif therapeutic antibody that inhibits relapsing MS (in phase II trials) also affects Natural Killer cell function, so this may be a way to target this subset of cells without the side-effect problems (cancer and damage of heart muscle) associated with mitoxantrone use.

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