August 13, 2013
Joining a clinical trial to prevent breast cancer recurrence
BY Oliver Bogler, Ph.D.
I finished the most active treatment phase for male breast cancer in the first week of June, enjoyed a few weeks off from regular clinic visits and am now back to join a clinical trial that I hope will help me stay disease free and make a contribution to the development of a new therapy to suppress breast cancer recurrence.
The trial is testing a relatively new approach, in which the immune system is trained to keep a watchful eye out for breast cancer cells. It is part of the exciting new breakthroughs that have occurred in the last few years, which are beginning to fulfill the promise of harnessing the immensely powerful immune system for the fight against cancer. One of the big challenges has been identifying the right way to train the immune system, both in terms of providing it the right target, and in knowing how to get it into high gear.
The trial I am joining was designed by Beth Mittendorf, M.D., in Breast Medical Oncology, who recently spoke about her work in an interview at ASCO.
Anatomy of a clinical trial
It is called "Prospective Randomized, Single-Blinded, Multi-Center Phase II Trial of the HER2/neu Peptide GP2 + GM-CSF Vaccine versus GM-CSF Alone in HLA-A2+ OR the Modified HER2/neu Peptide AE37 + GM-CSF Vaccine versus GM-CSF Alone in HLA-A2- Node Positive and High Risk Node-Negative Breast Cancer Patients to Prevent Recurrence."
That's quite a mouthful - it's almost a summary of the whole trial! Let's break it down.
The overall goal of the trial is to help the immune system with surveillance of breast cancer cells that might have survived all the other treatments. I know it's hard to believe that after 6 months of chemo, surgery and 6 weeks of radiation that there are any cancer cells left, but the fact that some people experience a recurrence of their breast cancer even decades later suggests that there might well be.
In fact, recent research has begun to focus on the dormancy of cancer cells and one hypothesis is that some of the cancer cells hide in your tissue in this dormant state, sometimes for years. The treatment that this trial is testing attempts to help keep any cells that wake up in check, by drawing attention to the Her2 protein.
Focusing the immune system on Her2
You have no doubt heard of Her2, and are aware of Her2-positive breast tumors and the availability of Herceptin as a treatment for them. Breast cancers that are commonly referred to as Her-2 positive have very high levels of Her2 protein, which makes the Herceptin treatment effective.
What is less commonly realized is that many breast cancers, at least of the most common luminal subtypes, express more Her2 than normal cells, even if they don't express the ultra-high levels that earn them the Her2+ designation and the option to be treated with Herceptin. This includes many male breast cancers. The good news is that this makes Her2 a good flag by which to recognize these cancer cells, and so a good tool to train the immune system to keep any remaining cancer cells in check.
The trial focuses the attention of the immune system on Her2 with one of two peptides, which are called GP2 or AE37. These are small bits of the Her2 protein, and are known to be good epitopes, which is the term for a structure that is good at attracting the attention of the immune system.
Imagine that you are trying to identify a car that is passing fast at night. Not all parts of the car may be clearly visible. The headlight is likely to make a stronger impression on you than, say, the door. You could teach someone who had never seen the car to recognize it by showing them only the headlight if it was sufficiently distinctive (i.e. a good epitope).
Like Xbox or Playstation, same game, different platforms
Why do we have two peptides, doing the same thing? Well, this is for simply practical reasons. It turns out that in some people GP2 works well, and in others AE37. The machinery that the immune system uses to recognize the peptide comes in different versions. Here the trial distinguishes between people who are HLA-A2 positive or negative. HLAs are part of the immune system, and you can think of them similar to blood type. HLAs are sort of like the platform the immune system uses to recognize abnormal or foreign bodies, and depending on which platform you happen to have, the trial uses either the GP2 or the AE37 peptide.
You can think of this as playing a video game on Xbox or Playstation - it's the same game, but if you have the Xbox disk (here peptide) you aren't going to be able to play it on a Playstation (HLA). The peptide and HLA have to be compatible. Patients are first typed for HLA-A2 type and then assigned to the appropriate group.
So what is the GM-CSF? This is a cytokine, a member of a large class of molecules that immune cells use to communicate. When, in the normal course of an immune response to say a bacterial infection, one immune cell wants another one to pay attention to the bacteria, it can use such cytokines to attract their attention, and actually allow them to proliferate. In this trial it is a critical tool to activate the immune reaction to the Her2 peptides. Without it, the immune system, which is bombarded by many signals every day, could miss that this Her2 thing is something to which it should really pay attention.
Help the immune system remember the enemy
The trial requires several rounds of immunization with the peptide-cytokine cocktail. Why? This is because we know that repeated exposure to an antigen is another good way to get the immune system to pay attention. There is a part of the immune system that keeps a memory that makes you immune. This is why getting vaccinations as a kid can protect you for many years. And the immune system benefits from repetition, just like a kid learning their vocabulary.
Preliminary results from trials of this kind are quite promising. A recent publication showed that 2-year disease free survival was increased by around 10% for lymph-node positive patients with low and intermediate levels of Her2.
Furthermore, none of the participants who received booster inoculations have experienced a recurrence of their cancer. If this pattern holds up it is possible that this treatment will be approved by the U.S. Food and Drug Administration and become generally available before too long.
Oliver Bogler, Ph.D., is MD Anderson vice president for academic affairs. He blogs about his experience with breast cancer at Cancerwise.