Well, it seems that I may stand corrected. In my October 8th post on CD40, I mentioned my doubts concerning the possible use of a modified cold virus delivery system for myeloma patients, but yesterday morning I read a few items that, hmmm, may have changed my mind. I will proceed in order.
All plasma cells express CD40, but that is not the case with all myeloma cells. According to a 1994 French Blood study (see: http://tinyurl.com/ywcyv4), two-thirds of myeloma patients express CD40. That means that one-third are CD40-. By the way, in case you had any doubt concerning the importance of CD40 for myeloma, read this excerpt: …patients with progressive myeloma present a high level of CD40 expression.
Regardless of whether your myeloma expresses CD40 or not, though, the important concept contained in a 2002 Blood study (see: http://tinyurl.com/ytv929) is that we should be able to stimulate our immune systems to react against the malignant cells if we are able to deliver a transgenic (genetically modified, basically) form of CD40L (= CD40 ligand or CD154) to either type of myeloma cells, whether it has CD40 on its surface or not. The study ends: because our results show that the interaction with CD40 antigen on tumor cells is neither universal nor required for the immune enhancement mediated by transgenic CD40L, the molecule may be of therapeutic value in both CD40+ and CD40- forms of the disease. So all bases are covered. Excellent.
Now, if we connect this study with the modified cold virus theory, we may have a delivery system, a system that is being tested in clinical trials for other types of cancer right now. I am getting to the good part, hold on.
I did research for and wrote this post after reading two very interesting Ph.D. thesis abstracts (Baylor University). The first, dated February 2007 (abstract: http://tinyurl.com/yqwr6l), is titled Anti-tumor properties of CD40 ligand when delivered as a transgene by the conditional replicative oncolytic adenovirus AdEH to breast cancer cells (try saying that out loud without stopping to take a breath!). The abstract informs us that a potential limitation of CD40L therapy is systemic toxicity. The good news, however, is that this toxicity can apparently be overcome by using an adenovirus, which is essentially a virus that causes upper respiratory tract infections.
Ahhh, a modified cold virus, perhaps? 😉
I have requested authorization to read the full text of the second Ph.D. thesis, dated March 2007 and titled: Growth inhibition of human multiple myeloma cells by a conditional-replicative, oncolytic adenovirus armed with the CD154 (CD40-ligand) transgene (abstract: http://tinyurl.com/25dsdk). The abstract informs us that for targeted delivery of CD40L, we have constructed a conditional-replicative adenoviral for delivery of the CD40L transgene (AdEHCD40L). So here we have a sort of Federal Express delivery van, that is, an adenoviral delivery system. The van is supposed to deliver a “lethal package,” that is, a genetically modified form of CD40L, called AdEHCD40L, to its CD40 “customer” located on the surface of myeloma cells. The delivered transgene, our FedEx package, then inhibits the growth of CD40+ human myeloma cell lines. Simply put, adenovirus plus modified CD40L equals no myeloma cell growth.
I admit that I am becoming a bit obsessed with these darned molecules. When I was a child, many many years ago!, I used to spend hours putting puzzles together. The more complicated and the more pieces there were, the better. Well, this molecule business is like a big virtual puzzle. Every day I seem to come upon a new piece of the puzzle. I will, however, stop before my brain melts.
Not yet, though!
As you know Margaret, I try to follow your research findings posts, because there seem to be many common underlying biochemical pathways between things that might help MM and those that might also help my wife Mary’s Alzheimer’s. During my research for her I often encounter detailed/complicated research studies, similar to those you report on here, which I do not fully understand, but do understand enough to put them away for referral in my “Looks promising if we can only hold on for another three years” directory.
The second PhD thesis (called Growth inhibition of….. the CD154 (CD40-ligand) transgene ) certainly looks very promising, even though I don’t really understand it very well, and I would suggest putting it in your “Looks promising if we can only hold on for another three years” directory.
I must warn you though that the three year time reference in my directory name used to be two years, and now I am ready to change it again–this time to five years. Because the wheels of drug development reseach grind exceedingly slowly.
I marvel at your ability to find and digest the meaty nuggets from these almost indecipherable research papers, and thank you most sincerely for your tremendous efforts on all our behalf.
Margaret,
Forget translations and try for a PhD in biochemistry. You’re a natural.
Thanks for sharing all this with us.
Paul
Thanks, Paul! I already have one Ph.D. and the mere idea of going back to school for a second one makes me dizzy! Very kind of you, though!
Wally, I agree with you about the AD and MM connections. As for thanking me, I appreciate it, but please remember that I am conducting this research also to find a treatment for my own condition, so it is not entirely selfless! Concerning those meaty nuggets, well, sometimes I fear I will make huge mistakes in interpreting them. If this should happen, and the following appeal is addressed to all of my blog readers, please let me know. I believe that humility should be a fundamental characteristic of any researcher. So I am ready to eat a slice of humble pie at any moment. 😉 The CD40 research is interesting, but as you said, let’s sit on it for a few years. Right now, nothing in the world would make me have an adenovirus injected into me! I’m sticking to curcumin and a good sense of humour! 😉 Thanks, Margaret