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Terry Hamblin |
My position on
rituximab and G-CSF is like any scientist's should be. I have an open
mind. My first reaction was that granulocytes take no part in ADCC and
therefore there was no reason why G-CSF should work. GM-CSF seemed a
better proposition, even though it is no longer available here in the
UK. However, GM-CSF is more toxic and in real life it seemed to have
very little difference in its clinical effect from G-CSF, which is why
the Company has withdrawn it here.
We have an experimental anti-CD20 antibody here, that is being tried in
various types of lymphoma. Before anybody asks, I should say that this
is not an invitation to participate in clinical trials. We are not at
that stage yet. In the test tube and in the guinea pig, this formulation
is more active than Rituximab. But in our first few patient studies it
has produced a very low white count, such that we needed to give G-CSF
as support. Now, one of these patients who had failed rituximab went
into a very good remission - lost her requirement for red cell
transfusions and platelets rose dramatically. So I ask myself whether it
was an interaction between the antibody and G-CSF.
I have been trying to see whether this is a possibility by asking and
reading around. I asked, could granulocytes participate in ADCC?
Although most scientists are think not, some think that they might have
a minor role. Then I asked can G-CSF affect macrophage function? Again
it seems that it might. It seems to be able to activate macrophages,
though unlike GM-CSF it cannot make them proliferate.
The immune response cannot be neatly separated into components. The
whole system is very complex, operating in a mixture of chemicals
(cytokines, chemokines, integrins, addressins etc) that mediate the
function of the cells involved. It had been thought that GM-CSF nudges
the immune response in the direction of a TH1 response while G-CSF
nudges it in the direction of TH2. Generally a TH1 response is favored
by the pundits. However, these impressions all come from experiments in
mice, which may not reflect the human situation. Even things like taking
an ibuprofen tablet might change the polarity of the response.
There is also evidence that activation of granulocytes is necessary to
kick-start the whole immune response (what used to be called a 'danger
signal').
So in the end it all comes down to clinical experiment, which is why I
am in favor of this study. If there is a consistent benefit in a large
proportion of people using it, then undoubtedly the medical
establishment will turn to it. There is a quote from Acts of the
Apostles that is apposite, The Jewish teacher, Gamalial, said, "If their
purpose or activity is of human origin, it will fail. But if it is from
God, you will not be able to stop these men." (Acts 6 v 38). I'm not
saying that there's anything Godlike about G-CSF, but if it works we
will know, and if it doesn't work we'll know that too. |