I stopped working for a while on the possible viral connection to myeloma (nope, I haven’t forgotten all your messages and contacts–it’s just that it is going to take some time to finish reading and attempting to understand all the studies and notes…I now have accumulated an overwhelming amount of material, which I am going through alone…so please please be patient… 🙂 ) to have a look at a brand new study published in “Blood”…one that sounds quite promising. It concerns an anti-myeloma “dendritic/tumor cell fusion” vaccine that has been tested in a Phase I study on myeloma patients…
When I first read the abstract, I was intrigued enough to ask a kind friend (thanks!) to retrieve the full study for me. Here is the abstract: http://bloodjournal.hematologylibrary.org/cgi/content/short/blood-2010-04-277137v1
As we can read, this was a phase I study in which patients with multiple myeloma (MM) underwent serial vaccination with the DC/MM fusions in conjunction with GM-CSF. Uhm, whaaat? Okay, con calma, as we say in Italian: 1. GM-CSF stands for Granulocyte-Macrophage Colony Stimulating Factor and is basically a substance (a cytokine) that stimulates the production of white cells; 2. DCs are dendritic cells, which are the main guardians of our immune system. Whenever our bodies are attacked by viruses or bacteria, the dendritic cells are the first to alert all the other immune cells of the danger. In cancer patients, though, DCs are defective…not surprisingly…hah.
Anyway, the study states that the anti-myeloma vaccine worked (more or less, as we will see) for 17 out of 18 myeloma patients, most of whom remained stable for varying periods—between 2.5 months and 41 months. 41 months is almost three and a half years. Not bad. Hmmm, but wait a sec, what about patient number 18? The full study solves the mystery: he/she was excluded from the study because of inadequate cell yields for vaccine generation. Ah, okay.
The vaccine was well tolerated without evidence of dose limiting toxicity. This is also very good news. The full study provides more details (see below…).
Okay, let’s go. The full study begins with a brief mention of the various therapeutic options offered to myeloma patients, pointing out that none are curative, not even autologous stem cell transplants, due to the eventual emergence of resistant disease. In contrast, the researchers add, the unique efficacy of cellular immunotherapy is supported by the observation that allogeneic hematopoietic stem cell transplantation is curative for a subset of patients due to the graft versus disease effect mediated by alloreactive lymphocytes. The problem with allo transplants, as we well know, is that only a tiny percentage of patients survive them…Well, this has little to do with the point of this post, so let’s proceed…
One important point: donor-derived cells (i.e., those used in allogeneic stem cell transplants) don’t specifically target myeloma cells, which, in addition to the regimen related toxicity, give rise to GVHD, or graft versus host disease. So this group of researchers looked at developing a “specific” vaccine that would stimulate the immune system to eliminate malignant cells and eradicate residual disease persisting following biologic therapy and autologous stem cell transplantation. And they developed a selective, autologous dendritic/tumor cell fusion myeloma vaccine…
Skip skip skip…overly technical bits. Ah, here we get to an interesting part…What type of patients participated in this Phase I study? A total of 18 patients, 12 men and 6 women, average age: 57, were found eligible. Most of them had active myeloma and had received at least 1 prior treatment regimen. 14 patients had previously gone through high-dose chemo and autologous SCTs…
Oh holy cats,! I almost fell off my chair when I read the subsequent sentence: In addition, patients with stage 1 myeloma who did not require therapy and were otherwise being observed were eligible. STAGE ONE MYELOMA PATIENTS???!!! This is such a vital bit of information! As you can imagine, my interest was piqued…went sky high, in fact…
Moving on: Patients must exhibit at least 20% involvement of the bone marrow with myeloma cells to facilitate vaccine generation. Patients must not have been treated with chemotherapy, steroids, radiation therapy, or immunotherapy within 4 weeks of study enrollment. Patients with a history of clinically significant autoimmune disease or organ dysfunction as measured by a bilirubin > 2.0 or creatinine > 2.0 were excluded. During the study, a patient developed a heart problem (unrelated to the therapy, though) and was excluded…
The researchers compared the patients’ post-vaccination CD4+ and CD8+ T cells to their pre-vaccination levels. Of 15 evaluable patients, 11 patients demonstrated at least a 2 fold increase in the percentage of CD4 and/or CD8+ tumor reactive T cells. That means that in 11 patients, the vaccine was able to stimulate the immune system…in a specific manner…
The vaccine was also well tolerated, as we already knew from the abstract. A few more details: at the most, there were a few grade II events (listed in a Table at the end of the study), but nothing major, from what I could tell. Oh wait, there was one, possibly related, pulmonary embolus (Grade 4), though in the Discussion part the researchers note that this particular patient had a prior history of DVTs. Most of the reactions were at the “injection site” = itching and redness. There were also a few instances of fatigue, diarrhea, etc., but nothing that really stands out to me, apart from that Grade 4 case., which might not be related…
Another important point is that vaccination did not result in signs of autoimmunity or suppression of blood counts, meaning that the vaccine didn’t have any bad effects on the patients’ red and white cell counts. Good.
So what happened to these patients in the long run? Of 16 evaluable patients, 11 patients demonstrated stable disease following vaccination. Three patients have ongoing stable disease following vaccination without evidence of progression at 12, 25, and 41 months. An additional 8 patients exhibited disease stabilization for 2.5 (4 patients) 3, 4, 4.5, and 5 months following vaccination. This sentence, and the use of the past tense “exhibited,” implies that the myeloma of eight patients did progress after 2.5, 3, 4, 4.5 and 5 months…Phooey, that titbit puts a bit of a dampener on things, doesn’t it? Three patients out of eleven…That is less than 30%…Oh well. And there is also no more talk of disease “eradication,” only “stabilization,” which is another dampener…
Well, let’s proceed to the Discussion part of the study: an interesting thing about this vaccine is that it is autologous and tumor-SPECIFIC. The vaccine, that is, was composed of a mixture of the patients’ myeloma and dendritic cells, with a few other things thrown in, such as GM-CSF…
Here the researchers surmise that patients in less advanced stages of myeloma might have a longer-term response compared to those in a more advanced stage of myeloma. And, in fact, they point out that it is not easy to interpret the study results because of the differences between the myeloma patients enrolled, most of whom had advanced and heavily pre-treated myeloma…
But hey, let’s not forget about those two patients in Stage 1. I went through the study carefully (or so I think!), looking for more information on them but found nothing. I wonder if they were the ones who had the most positive reactions to the vaccine…the ones that remained stable at 25 and 41 months? It makes sense, but I have no proof of that, just a hunch that might actually turn out to be more than a hunch, since the researchers note that patients with a lower disease state might fare better than those with bulky disease…In my view, if that were the case, the position of the vaccine would be weakened. However, if that were not the case, said position would be strengthened. I mean, it is one thing if the anti-myeloma vaccine kept a Stage 1 patient stable (the patient might have remained stable anyway), quite another if the patient were in an advanced stage of myeloma…Well, this is pure speculation on my part, of course.
Obviously, more studies are needed…and more patients need to be recruited, especially those in early stages of myeloma and/or, as the researchers themselves indicate, those who have recently undergone autologous SCTs…
I have to admit that I teared up a bit as I read through the Discussion. I mean, just think about it: at some point in the future the cure for myeloma might be a simple vaccination or a series of vaccinations. Wouldn’t that be fabbbulous? But the fact that the vaccine worked well only in three (our of eleven) cases makes me think that we are still quite far from that goal…
However, in spite of all the dampeners that I have mentioned, I am feeling optimistic and look forward to reading more on this topic…
