As we learn more and more about cancer, we begin to find characteristics of cancer cells that betray their identity in a way we can attack. One example: Many types of cancer cells have a specific mutation in a protein called IDH1 that normal cells don’t have. The mutation in that protein changes its structure enough that you can induce antibodies to go after it but leave the normal protein — and hence normal cells — alone.
Researchers based in Heidelberg, Germany, led by Michael Platten, have done just that, as they reported March 24 in Nature. They developed a brain cancer vaccine, and the first real tests in humans show that brain tumors are being infiltrated by T cells programmed to go after this protein, and in most cases the progression of the disease is being halted.
We may just be on to something here, folks.
Around 2007, it was noticed that colorectal cancer cells in a particular case had a mutation in the IDH1 protein. Then that same mutation started being noticed over the next decade in several other types of cancer. This mutation is called R132H, which means that the 132nd amino acid in this protein (which is 414 amino acids long) has the usual arginine (R) replaced by histidine (H).
IDH1(R132H) is especially common in gliomas. These are brain cancers that originate in the glial cells, such as glioblastoma multiforme, which Sen. McCain succumbed to. But this mutation can show up in other types of cancer as well.
Other similar variants of it have popped up, too. Sometimes it occurs in the IDH2 protein, which has the same function as IDH1 but is located in a different place in the cell.
So what does IDH1 do, and why are mutants of it showing up in so many cancers?
IDH1 is an enzyme called isocitrate dehydrogenase. It is there to catalyze (greatly speed up) the reaction we see on top below. But when IDH1 gets mutated with R132H, it stops doing that and instead catalyzes the reaction we see on the bottom:
The top reaction, where isocitrate gets converted into α-ketoglutarate, is a super-important part of your metabolism. I won’t draw out its entire metabolic neighborhood, but I can say that without IDH1 and IDH2 you would not be able to breathe, derive energy from food, or make proteins. So, it’s something you kind of like to have.
The bottom reaction, on the other hand, is pretty diabolical, because it changes α-ketoglutarate into an impostor of itself, 2-hydroxyglutarate. These two molecules are exactly the same except that the latter has an —OH instead of an =O.
So 2-hydroxyglutarate goes around the cell posing as α-ketoglutarate. In doing so, it gets in the way of the functions that α-ketoglutarate is supposed to be carrying out.
You have two copies of the IDH1 gene (which codes for the IDH1 protein), so when one IDH1 gene gets mutated, the other is still normal. So a tumor with an IDH1 mutation still has one good IDH1, and so it has all its metabolism together and can still grow, but now it’s also got this rather evil new function.
Here’s the problem: One of the key things that needs to go on for a cell to have the proper identity is the demethylation, or removal of —CH3 (methyl) groups, from DNA. If cells can’t do that, they can’t differentiate, and they can end up growing into unstoppable blobs (tumors). Demethylation of DNA is handled by “TET” enzymes, which depend on α-ketoglutarate. But now the impostor 2-hydroxyglutarate gets in the way of that.
As if that weren’t enough, 2-hydroxyglutarate can also suppress your immune system overall, helping a tumor to escape the immune response. So we’ve turned the very helpful molecule α-ketoglutarate into a molecule that is essentially a big jerk.
One slight saving grace of the IDH1 mutation is that because one copy of IDH1 is defective, cell metabolism can be a wee bit slower, and this hampers tumor cells’ growth just enough that the prognosis is actually a bit better for cancers in which there is an IDH1 mutation. That doesn’t mean good, just a little better.
If a patient does have a tumor with the IDH1 mutation, you will see elevated levels of 2-hydroxyglutarate (abbreviated D2HG below), and fortunately that is detectable:
You can do it by biopsy, but now also even with MRI. The other bit of good news is that the mutated form of IDH1 looks different enough from normal IDH1 that antibodies can tell the difference. You can too, if you look carefully:
The mutation seems to make one of the curlicues (helices) near the center swing over to another location.
So, will an antibody to IDH1(R132H) actually be able to attack tumors on this basis? Can the immune system spot those proteins, even though they are inside cells?
The answer is yes, indeed. This was a small trial (33 patients), but it’s important that this was done in humans and not mice. The results, though they still have to be regarded as preliminary, are quite encouraging.
Nearly all the subjects, with the help of the vaccine, developed an immune response to IDH1(R132H), and among those that did, 82% showed no progression of tumors for two full years. The two unfortunate patients that did not develop an immune response did show progression after two years.
Some of the patients with a good immune response showed something called pseudoprogression. That means the tumors appeared to have grown, except they hadn’t; they were swollen because T cells were attacking them!
Lead researcher Michael Platten is cautious, of course, but still very optimistic:
"We cannot draw any further conclusions about the vaccine efficacy from this early study without a control group," remarked Michael Platten. "The safety and immunogenicity of the vaccine were so convincing that we continued to pursue the vaccine concept in a further phase I study." In this follow-on study, the researchers are combining the IDH1 vaccine with checkpoint inhibitor immunotherapy. "Checkpoint inhibitors act as an immune boost. We believe there is a good chance that they can activate the immune cells against the gliomas to an even greater extent."
Don’t get too comfortable, cancer. You have always put a lot of obstacles in our way, but we’re still comin’ to git ya….