Mutations in CD20 can cause resistance in rituximab treated lymphoma
NHL Source: Sanford Health / NCI
A while back, I was discussing Non-Hodgkins Lymphoma (NHL) with someone and we pondered the question, “Why do some patients develop resistance to therapy with rituximab and others do not?”
The answer wasn’t immediately obvious at that time, but this morning I was delighted to spot a published article while browsing Flipboard, a nifty iPad app that brings turgid RSS feeds from journals to life and makes them interesting again.
It turns out that a Japanese group figured out the problem of what, in that Terui et al., (2009) discovered the root cause lay in CD20 mutations, but they they didn’t know the how or what. This month, in one of the Nature publications, Blood Cancer Journal (Open Access, see references below), the same group have now expanded on their earlier findings. Mishima et al., (2011) discuss how mutations in CD20 constitute part of the mechanisms that cause resistance rituximab therapy, specifically:
“In this study, we revealed that the binding site of L26 monoclonal antibody is located in the C-terminal cytoplasmic region of CD20 molecule, which was often lost in mutated CD20 molecules.
This indicates that it is difficult to distinguish the mutation of CD20 from under expression of the CD20 protein.”
The basis behind this research is that if “expression of CD20 seemed to have been completely lost for these lymphomas” how can we essentially unhide them? In non-science speak, it’s as though they are protected by a Klingon-like shield to rituximab.
By finding the binding site on the C20 molecule, the researchers were able to develop new antibodies to the N-terminal region to identify cells that “have CD20 molecules with abnormalities in the C-terminal cytoplasmic region.”
The upshot of all this is that while the resistance is thought to be irreversible, the findings may help us identify patients who need a change in treatment earlier:
“This information may provide important criterion to judge whether it should switch to the treatment such as using second-generation CD20 antibody that is effective against fewer CD20-expressing cells.”
The group suggested that it may also be possible to consider using “using antibody for the different target molecule such as CD22.”
Time will tell what happens here, but these developments are important in our understanding of rituximab resistance in lymphoma.
Notes for PSB Readers:
For those of you with an iPad, you can download Flipboard from iTunes. Once you have put all RSS feeds from your favourite journals, publications and news sources in to a Feedreader such as Google Reader, you can then import the aggregated feed into Flipboard and browse the articles more easily.
References:
Mishima, Y., Terui, Y., Takeuchi, K., Matsumoto-Mishima, Y., Matsusaka, S., Utsubo-Kuniyoshi, R., & Hatake, K. (2011). The identification of irreversible rituximab-resistant lymphoma caused by CD20 gene mutations Blood Cancer Journal, 1 (4) DOI: 10.1038/bcj.2011.11
2 Responses to “Mutations in CD20 can cause resistance in rituximab treated lymphoma”
the real question is: how often resistance to treatment as a whole (R-chemo) is related to R as opposed to chemo. I suspect – for lack of solid epi data – that resistance is rather due to all the known mechanism of escape to chemo rather than what appears to be a rare mutation.
Good question, but a little hard to answer without much data our there, especially sicne few patients are likely to receive R without CHOP. It would be interesting to see what preclinical models show on this as a starting point.
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