Thursday, May 6, 2010

My frustration with 3F8

People often ask me, "Which is better, 3F8 or ch14.18?" The answer is always a tricky one. To this day, my answer is mixed. Sometimes I believe that 3F8 is better and sometimes I know ch14.18 is better. In fact, I even know when those times are. Right now, I can end all debate and tell you without a doubt when 3F8 should be better and when ch14.18 is better. Unfortunately, as you will see, although I am technically correct, the answer still provides you little direction.

First, I should tell you that the entire basis on which my antibody revelation is built upon is theoretical. It is my belief. However, I think I can make a pretty clear argument. So, here goes.

I believe more antibody is better than less. We already know from published research that both ch14.18 and 3F8 are dose dependent. In other words, the more antibody you get the better effect it has. We have seen this in "petri dish" science but it has also been reiterated in animal studies and early phase kiddo trials. We know that, at least up to the points that we have been able to safely test, that more dose appears to be more effective.

My "theory" is that, along with a higher dose, more doses is also more effective. This has not been studied extensively. However, I can tell you from personal communication with doctors from Sloan that, up to a point, this has been their experience as well. Bottom-line, overall, kids that get only a few rounds of 3F8 don't fair as well as those that receive 6, 7, 8 or more.

Could this be because those that only receive a few rounds aren't exposed to enough antibody to get the job done. Quite possibly, and that is the answer that, for the time being, I am sticking with.

So, if you buy into that theory, then the answer should become clear. With all else being equal, the antibody that you get the most of is probably the better one. As of this date, you can only receive 5 rounds of ch14.18. With 3F8 you can receive as few as 1 or as many as 13 (or more in certain situations) With ch14.18 you are pretty much guaranteed to get your 5 rounds unless there is some kind of strange toxicity. However, with 3F8 you are not. 3F8 has the HAMA problem. HAMA is Human Anti Mouse Antibody which is an immune response to 3F8 which prevents the antibody from doing its job in humans. Unfortunately you never know when (or if) you will develop a HAMA. It could be the first round it could be the last. You may just be able to receive 2 rounds or you may be able to receive more than 5. However, it is an unknown. ch14.18 has a similar response called a HACA, however, it is generally less severe and occurs far less frequently. And, unlike the HAMA with 3F8, I have never heard of it preventing further treatment.

So, in the case of a patient that is going to HAMA before round 6 ch14.18 is the better antibody. For those that won't HAMA, the correct antibody may be the 3F8. The problem is that you don't know which group your child will be in. Furthermore, given the fact that we know that the ch14.18, when given with IL-2 and GM-CSF in the post transplant setting, increases 2 year survival by about 20%, it is a big gamble. It is risky to try 3F8. You are gambling that 20% increase in survival on my "theory" that more is better by hoping that (a) you will not HAMA before the sixth round and (b) that I am actually right.

It is a stretch.

Now, many are going to argue that 3F8 is a better antibody than ch14.18 because it is more immunogenic, because of its come off rate, or because of 10 other theoretical arguments. I will be glad to argue all of those until we are blue in the face but the thing I think we should all remember is that in human beings with neuroblastoma both have had very similar response rates. If one is better than the other it surely isn't showing itself in the patient responses. And, if it isn't, do the theoretical arguments really matter at this point anyway?

Now, why am I frustrated? Because of the HAMA! 3F8 is the only antibody that we can get more doses of at this point and it is also the only "worthwhile" option for patients looking for antibody post relapse (ch14.18 is not available currently to this population). Furthermore, I am extremely tired of seeing kids either HAMAing early or receiving unnecessary chemo to prevent the HAMA.

I wish there was another answer.

I guess that is what continued purpose is for.

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