Research Article: The Potential Effect of Statins on Rituximab Immunotherapy

Date Published: March 25, 2008

Publisher: Public Library of Science

Author(s): Mark S Cragg

Abstract: The author discusses a new study showing that statins have an inhibitory effect upon rituximab treatment.

Partial Text: CD20 is a cell surface marker expressed on mature B cells and most malignant B cells. It does not modulate rapidly, is not shed, and is highly expressed, leading to its use as a target for immunotherapy. In 1997, rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), was approved for use in the treatment of cancer following its efficacy (46% response rate) in a phase II trial involving 37 patients with relapsed low-grade non-Hodgkin lymphoma [1]. Since then, rituximab has been approved for the treatment of numerous other B cell malignancies and is now being actively investigated for use in the treatment of autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus [2,3]. As a result, rituximab has been administered to more than a million patients worldwide, making it the most successful immunotherapeutic (commercially and clinically) used to date.

In a new study published in this issue of PLoS Medicine [16], Jakub Golab and colleagues address this very issue: namely, how do statins affect rituximab treatment? Perhaps surprisingly, they show that instead of enhancing the ability of rituximab to kill target cells, statins are inhibitory.

Given the potential implications of these findings, the next steps are to confirm them and then to establish the CD20 status of patients on long-term statin treatment. Subsequently, it will be important to address whether equivalent effects on CD20 binding are observed in patients suffering from malignant or autoimmune disease to determine whether B cells in these conditions are more or less susceptible to the effects of cholesterol depletion through statin treatment. Previous in vitro experiments with methyl-beta-cyclodextrin indicate that the effects of cholesterol depletion on CD20 mAb binding are highly dependent upon both the mAb and cell type [24,25]. Presumably, data on the effects of statins on rituximab use are already available through retrospective analysis, as it is likely that among the million patients treated with rituximab a proportion were also receiving statins. To date, very few cases of co-administration have been reported, but it is important to note that in at least one of these, long-term statin treatment did not appear to impair the normal therapeutic effect of rituximab [26]. These data, coupled with the limited effects seen in Figure 9 of Golab and colleagues’ study [16], suggest that the pronounced effects of statin treatment on anti-CD20 binding observed on lymphoma cell lines in vitro may not translate to equivalent effects in vivo. However, note that the CD20 binding shown in [16] was assessed after only a three day treatment with atorvastatin; potentially greater effects would be observed after more protracted treatment. The definitive answer to the question of whether statins substantially affect CD20 binding and function in vivo awaits clinical investigation.

Interestingly, Golab and colleagues reported (but did not show) that inhibitors of farnesyltransferase and geranylgeranyltransferase did not decrease CD20-mediated CDC [16], indicating that the effect of statins on anti-CD20 mAb binding is independent of their effects on impaired protein prenylation. As prenylation inhibition is a central component of the anti-tumor effect of statins [10,13,27,28], it is possible that farnesyltransferase and geranylgeranyltransferase inhibitors such as tipifarnib may work well in combination with rituximab. To discover if this is the case, a sensible way forward would be to examine the direct cell-killing activity of these reagents in combination with rituximab. Whether this combination will also fall foul of unexpected complications remains to be seen.

Source:

http://doi.org/10.1371/journal.pmed.0050077

 

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