Dr. George Peoples, Director of the Cancer Vaccine Development Program and Chief of Surgical Oncology at San Antonio Military Medical Center (SAMMC), talks about what’s helping women who’ve fought breast cancer once, from fighting it again.
What is E75?
Dr. George Peoples: E75 is actually a piece of the HER2/neu protein which is only expressed in large amounts on cancer cells. This peptide happens to be a very important piece because it is the point of recognition for the immune system. Killer T-cells that fight disease, recognize these small pieces of proteins that are presented to them by HLA molecules. That combination of HLA molecule and peptide is what stimulates the killer T-cells to do their job which is to kill that cell. E75 is that peptide or piece of a protein that is most recognizable to the immune system on certain cancer cells.
How does it work?
Dr.George Peoples: This researchhas been going on a long time and traces back to the idea that the immune system can in fact recognize and kill cancer cells. Once that concept became fairly well established, we began to look at the mechanism behind it. We began the search for the antigen that was being recognized and more importantly for the the piece of the protein that was most antigenic or recognizeable to the immune system. That work was all done in the 90’s, andE75 was originally described in 1995. We began working with this peptide shortly thereafter and began to turn this peptide into a vaccine. The idea was to use the E75 peptide with an immune stimulant together as a vaccine (now named NeuVax) to generate a robust response to get T-cells revved up and able to recognize and kill cancer cells. Once the vaccine had been validated in preclinical studies, we began the clinical process. The clinical testing process began with a phase I trial, which looked for the safety of using the vaccine and also the appropriate dosing of the peptide in order to get the most optimal immune response. Once we figured out the safety and dosing, then we began phase II which determines whether the vaccine can be clinically effective. That’s when we began to treat women to determine whether or not we could actually prevent recurrences of their cancer.
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So how confident are you from what you’ve seen in phase II and phase III that this will get approval?
Dr.George Peoples: If we see in the phase III trial what we saw in phase II, it will get approved, but that’s always the big question. We see a lot of promising phase II drugs that don’t do as well as in phase III, and a lot of times it’s because of the added features of phase III trials that make them so much more stringent.
What did you see in phase II?
Dr. George Peoples: In phase II, we actually had about 200 women with approximately half vaccinated and half followed prospectively as our control arm. Those women that were vaccinated had their vaccinations done once a month over six months. About half of those women went on to receive also booster inoculations that was a component of the trial that was added a little bit later. But all of the women both vaccinated, boosted and not boosted, as well as the control group were followed for 5 years. The last woman actually will complete her 5 year follow up this summer and that trial will be officially closed. What we have up to this point, pending the last few follow-ups, is about 20% recurrence rate in the control group and about a 10% recurrence rate in the vaccine group, so about a 50% reduction in overall recurrences.
That’s a pretty substantial number correct?
George Peoples: It is a substantial number. A lot of times when you hear about new chemotherapies or new regimens and new combinations of drugs being tested, they get approved based on a 10% improvement and here we saw a 50% improvement. We’re shooting for a substantial number in the phase III trial as well; it’s a reduction in recurrence by a third. So we’ve backed off of the 50% a little bit to try to make it a bit of an easier target to hit and increase the chances of the phase III being successful.
What is the normal recurrence rate right now?
Dr.George Peoples: The recurrence rate is based on the stage of the disease. Typically, we look at women as being node positive or node negative just as a general guide. Women who are node positive, which is the patient population that’s being targeted in the phase III trial, their risk of recurrence is somewhere around 20 and 25% at 3 years.
So why not just vaccinate every woman with NeuVax?
Dr. George Peoples: We’d love to get there, but we have to answer some key questions first. One of the issues will be whether or not this particular vaccine is going to be "the right vaccine" for using as a truly preventive vaccine. Another problem with prevention trials overall is that they take a long time to conduct. For example, I can take a group of women who have a known risk for breast cancer and vaccinate them, but it could be 20 years before a woman who is at risk actually develops the disease. So, it could take a very long time before I would know if I benefited anyone with the vaccine. So, we have tried to take vaccines into what we think is the appropriate setting which is to prevent disease, but to test in a group of people that we have some defined numbers around as far as the risk of recurrence and probably even more importantly time to recurrence. The group that I mentioned previously, the node positive women, we know that their risk is 20-25% and we know that rate is at 3 years. So, thatgives us a timeframe in which we can actually test a vaccine in a reasonable period. While it’s not primary prevention, it is prevention.
What makes you excited about this trial?
Dr.George Peoples: I think what is very exciting is the vaccine targets a protein called HER2/neu. Now HER2/neu became very famous because of Herceptin, a very popular and successful breast cancer drug that targets this same protein. The mechanism of action between the way Herceptin targets HER2/neu and the vaccine targets HER2/neu are very different , and as a result of that, it allows us to use the vaccine in patients who are otherwise not eligible to receive Herceptin. Even beyond that, the thing that really excites me about this is there are a lot of different cancers that express HER2/neu. Now we really don’t think about HER2 expression in them because they do not have that highest level of expression necessary for Herceptin use, but other cancers that come from an epithelial cell origin like all the most common cancers: lung cancer, colon cancer, prostate cancer, ovarian cancer do express some level of HER2/neu. Just as we target the 1+ and 2+ levels in breast cancer, theoretically those other cancers may be targetable as well because they do express HER2/neuat the 1+ and 2+ level.