Unless this is your first time to this blog (and if so, hi; take a look around and ignore the sarcasm long enough to realize I am actually a nice person), you know that I use a lot of pixels to chat about immunotherapy.
What you may not know (I honestly didn’t), is that apparently there’s a classification for melanomas that respond to immunotherapy. In a very strange version of the Hot or Not game, melanomas can either be hot – i.e. respond to immunotherapy to guide the immune system to destroy it – or cold (not) – i.e. immunotherapy provides little benefit. If your melanoma is hot, I suppose that’s good news in a way; although the best news would be if your melanoma was non-existent…
Anyway, the issue for melanoma patients and their doctors is that up to 50% of melanomas are cold. And I guess the even bigger issue is that there is currently not an effective test to prove one way or the other which type of melanoma you have. So the doctors administer immunotherapy and hope for the best. That can be very expensive in terms of time and money spent waiting to see if there’s any benefit or not.
So researchers at the University of Colorado Cancer Center are hoping that they might be able to solve the riddle of the “Hot or Not” question. According to a study presented at the American Association for Cancer Research Annual Meeting 2019 (that is a mouthful), they noted this intriguing finding: mutated tumors with genes that over-activate Nf-kB signaling pathways were more than three times likely to respond to anti-PD1 immunotherapy compared to tumors that didn’t have the Nf-kB signaling pathway activation genes.
Ok, in human terms it means that “hot” melanoma tumors have a tendency to have this mutation that makes the Nf-kB pathways get all crazy like pre-teens at a Bieber show (wait, is he relevant anymore? I’m not keeping up with what the kids are into these days). This might be a way for doctors to predict if your melanoma is hot or not, thereby more effectively determining if immunotherapy is the right treatment option for you.
You may be wondering, what the hell is a Nf-kB pathway anyway? Let’s break it down… Nf-kB stands for nuclear factor (Nf) kappa-light-chain-enhancer of activated B cells (kB). See, clear as mud, right? Now you’re thinking, what the hell does all that mean… Nf-kB is a protein complex, basically a boatload of proteins (does anyone remember that post about proteins – peptides are compounds made of amino acids, get enough amino acids together and a peptide becomes a protein). A protein complex like Nf-kB is a collection of proteins that work together to perform some action. It can get a lot more complicated than that explanation and you’re welcome to dive into the world of covalent bonds if you’d like but I got other stuff I want to do today…
So Nf-kB is a bunch of proteins that work together in your body (and pretty much every animal on the planet) to control DNA transcription, cytokine production and cell survival. If you’re coming down with a cold, Nf-kB is involved. If you’re stressed about an upcoming presentation or exam or meeting with your boss, Nf-kB is involved. If you’re growing new cells, Nf-kB is involved. Basically, Nf-kB is that person you know that gets all her work stuff done, exercises regularly, organizes the girls’ happy hour, and still manages to have a clean house. (I hate those people, seriously, don’t they know the joys of sloth?)
Nf-kB is heavily involved in your body’s immune response. And it’s classified as a “rapid-acting” transcription factor. This means that Nf-kB leaps into action at the first sign of immune trouble. Unfortunately Nf-kB is just like everything else in this imperfect world, it doesn’t always work correctly 100% of the time. Researchers have linked incorrect regulation of Nf-kB to cancer, autoimmune diseases, sepsis, and other undesirable outcomes.
Getting back to the University of Colorado Cancer Center study… If your Nf-kB pathway is overactivated, it may be a predictive tool for doctors to determine whether immunotherapy may work for you. There are some theories on why. One line of thinking is that if you have a tumor that is mutating like crazy, the difference between healthy tissue and the bad stuff is super easy for the immune system to spot and with a boost from immunotherapy, kill it off. Of course, the immune system is crazy complicated and it may be there are more subtle factors at play here.
So the research team looked at samples of melanoma they had from the Colorado Skin Cancer Biorepository, which totaled about 500 samples from 400 patients. They then asked which one of those patients had immunotherapy, looking to see if there was anything in the tumors that responded well to that particular type of treatment. Out of 52 people who got immunotherapy, only 21 had favorable responses to it. And out of those who got benefit from the immunotherapy, 67% had genetic differences associated with the Nf-kB signaling pathway.
As Carol Amato, senior professional research assistant at the University of Colorado Cancer Center said, “What we show is that cancers with alterations that over-activate the NF-kB may better benefit from immunotherapy.” And the really interesting thing is that due to a specific mutation in a negative regulator of Nf-kB (that is, a gene that basically put the brakes on Nf-kB action) called G34E – which in this study was only found in those tumors that responded well to immunotherapy – is that it didn’t matter if the tumor also had BRAF and/or NRAS mutations (which are common in melanoma tumors). In plain English, even if you have BRAF mutations which normally limit the effectiveness of treatments currently in use, looking at your activation of the Nf-kB pathway signaling may be a much better predictor of immunotherapy effectiveness than taking immunotherapy and crossing your fingers (and sadly, that is kinda current state right now).
While this study doesn’t really break new ground on curing melanoma, it does show the potential for a predictive tool for doctors to known whether anti-PD-1 immunotherapy will be effective for your specific instance of melanoma. And anything that can provide even a slightly better margin of error than a coin toss is an improvement.