What the heck is anti-EGFR therapy? (with an audible play call at the end)
I had a (relatively 🙂 ) quiet week, so I wanted to take the opportunity to write another “Common Question Answered” post to try to explain in easily understood language the new treatment I recently started for my CRC (an anti-EGFR therapeutic antibody called cetuximab). I’ve found that there is a real curiosity among both fellow patients as well as the general public to understand why certain drugs are used for cancer therapy, how they work and what it is like to take them from my patient experience. I think everyone has the right to know what a medicine is “doing in their body” & the science behind the medicines (especially the modern ones) is often fascinating! A goal of mine, initially while talking to patients 1-on-1, and now via my blog, is to try to help change that. There is a fine line between detail overload and over-simplifying too much, I’ll try my best to strike a careful balance!
In addition to explaining my current therapy, the second half of the post will be about an “audible play” I ended up calling after I was excluded from the clinical trial (i.e. many clinical trials) a few weeks ago. To paraphrase William Congreve (1697), hell hath no fury like an oncology scientist excluded from clinical trials! 🙂 For scientist readers who already know how anti-EGFR therapy works (or those not in a mood for a science class), you may want to just skip ahead to the second part of the post!
OK – I know you started a new therapy recently… How do I put this delicately… – you’re suddenly bright red and have more acne than an entire homeroom full of 15 year olds – what the heck are you taking and why?
OK – that was a bunch of words that barely sounded English. Let’s start off with the obvious question – what the heck happened to your skin?
EGF receptors are present not only in my tumors but also throughout the body including predominantly in the skin. Some studies suggest it is actually a good sign to see a skin rash when you are taking anti-EGFR therapy since getting a skin rash may = a higher chance that your tumors are being successfully targeted as well (but like all rules, there are patient exceptions in both directions). It was the first time ever that I started clapping & fist pumping (in private 🙂) the appearance of acne when it appeared! Woo-hoo! Take that cancer! My skin actually looks worse than it feels – it feels like a slightly itchy sunburn – not a big deal. I have felt no other side effects of the drug, e.g. no nausea etc
OK – No nausea? Wait – isn’t this anti-EGFR drug a type of chemo??
No, it’s not chemo. It is a type of modern cancer therapy called a “targeted therapy”. It only reacts with cells that have the EGF receptor (e.g. CRC tumors & skin) and the amount of reaction is dependent on how much of the receptor is present and/or how dependent the cell type is on EGFR signaling. Since many CRC tumors are especially dependent on EGFR signaling, that gives a nice “toxicity window” to attack the cancer via proper dosing – without being indiscriminately toxic to many other parts of the body (unlike traditional chemotherapy!). This larger toxicity window is why it doesn’t have the traditional chemo toxic side effects of nausea etc. Skin is an exception (it has a lot of EGFR), which is why you do get the skin rash as a side effect. Cetuximab, as an antibody is exquisitely selective for binding to the EGFR which also is an important reason behind its lack of side effects. Antibodies are more selective for their targets than most small molecules (e.g. most of the pills you take) could ever hope to be – but they require iv dosing, so I do still have to go to infusion center for treatment.
OK – I can see now why it has the different side effects than traditional chemo but I’m curious, how does it kill the cancer?
Ahhhhh, that falls into the realm of “sometimes simple questions have surprisingly complex answers”. I’m going to explain three of the big ways anti-EGFR therapeutic antibodies work against cancer – trying to strike that balance between not getting lost in the complicated details (the details are actually VERY complicated) but still giving you a feel for how it works. It is so complicated though, that these three big ways cetuximab fights cancer do not capture everything that is going on during the attack!
1.) Main mechanism of action #1: blockage of the EGFR signal transduction cascade.
From the name “Epidermal growth factor”, as you can guess, it is a receptor that when activated – in a broad general sense causes cells to grow. As a part of a normal living body this is good (and essential). Unfortunately in cancer, this process can be hijacked and used not only to help the tumor grow but also help the cancer invade other tissues (“metastasis”), abnormally grow blood vessels to feed itself (“angiogenesis”) and block cellular suicide (“apoptosis”) which normally occurs when cells aren’t behaving themselves. Since many CRC tumors are especially dependent on this hijacked process to grow, blocking EGFR can stop many tumors from growing and in some cases, even cause them to shrink. Cetuximab binds to EGFR, physically blocking the growth factor (EGF) from binding to the receptor. By doing this, it blocks the growth signal cascade from being activated. If this was the only anti-cancer mechanism, it would be amazing enough but wait… enter the immune system!
2.) Main mechanism of action #2: Immune cell destruction via “Antibody-Dependent Cellular Cytotoxicity (ADCC)”
A big part of the immune system is the “Adaptive Immune System” – this is the part of the immune system which e.g. uses antibodies to recognize and bind to dangerous things in the body to flag them for destruction by immune cells. For example, vaccination causes the development of antibodies against germs, allowing the body to quickly fight these germs off if a real version of the germ ever appears. Therapeutic anti-cancer antibodies hijack this system to good use – when the EGFR antibody drug binds to the cancer cells expressing EGFR, the antibody acts as a flag to get the immune system’s attention. Immune cells come streaming to the rescue and kill the cancer cell which has been flagged as being dangerous via having an antibody attached to it.
3.) Main mechanism of action #3: Immune cell destruction via “Complement-Dependent Cytotoxicity (CDC)”
The second big part of the immune system is the “Innate Immune System” – this is a more ancient portion of our immune system which does not have memory or utilize highly specific antibodies. In a less specific way, it recognizes potential dangers to the body and signals immune cells that there may be something dangerous present. Inflammation is an example part of the innate immune system. One portion of the innate immune system is the “Complement system”. This system helps activate non-specific immune cells towards attacking marked items of “potential danger”. The binding of Cetuximab to cancer cells causes complement signaling to activate cancer cell killing via CDC. But… the CDC killing is not activated to its full anti-cancer attack potential (see below).
That covers some of the major ways cetuximab has anti-cancer activity but as I mentioned, the total number of ways it does its work is very complex and involves even more components than I described!
Enter the annoyed (ok, perhaps mad) scientist
One issue with the Complement-Dependent Cytotoxicity mechanism mentioned above however, is that the immune system is not fully primed to be successfully activated by the cetuximab-bound cancer cell’s complement signals – this leads to the CDC not being activated to its full ability. In other words, a more fully functioning CDC would be expected to do a significantly better job of cancer killing. This has led e.g. to the scientific study of using purified beta-glucans (which are present in many foods e.g. mushrooms, barley & yeast) to try to prime immune cells and fully activate anti-cancer CDC.
Although beta-glucans have been used by numerous cultures for centuries as anti-cancer traditional medicines (most predominantly in the form of Asian mushrooms), it is only recently that their significant synergy with anti-cancer antibodies has been shown in pre-clinical models of cancer which has led to a number of experimental clinical trials in humans – in addition to active medical use in a number of countries, including pharmaceutical approval in Japan. Although this is purely conjecture, I wonder if the anecdotal accounts of beta-glucan anti-cancer activity reported over the years may have been seen in patients that harbored natural antibodies against their tumors which had not been fully efficacious until “helped out” by beta-glucan activated CDC. That is only conjecture but certainly there have been signs of efficacy in preliminary clinical trials of co-dosing beta glucans along with therapeutic antibodies such as cetuximab as well as significant efficacy in pre-clinical models of cancer.
It was for all of these reasons, that the clinical trial I attempted to enter a few weeks ago was comprised of co-dosing of a purified 1,3-beta glucan (iv) followed by cetuximab. Since I was focusing on low-toxicity treatment options, cetuximab was a natural contender for my next therapy. When I saw the preclinical data on 1,3-beta glucan co-dosing with cetuximab as well as hints of efficacy from a preliminary clinical trial and the known low toxicity, it seemed like an easy choice for me to try the trial.
But as you remember, I was excluded from the trial due to my melanoma, in fact excluded from many potential trials. Thus entered the extremely annoyed (ok, perhaps mad) scientist into the story.
Time to call an audible play
Now to begin with, I do not suggest that anyone else does this, I’m not a MD and I did this based upon making decisions concerning my own personal body & my own unproven scientific conjecture. I also did tell my doctor what I was doing because even for a Mad Scientist, the first rule should always be the medical principle “Primum non nocere – First do no harm” which is a component of the much longer Hippocratic Oath.
When I was excluded from the trial, I already knew the use of beta glucans over the centuries & currently by many naturopaths. As I said, there are certainly anecdotal accounts of anti-cancer activity but nothing had been proven in randomized clinical trials (thankfully the trial, which I was excluded from, is now in progress!). I had clues from published pre-clinical studies that beta glucan anti-cancer activity may require co-dosing with an anti-cancer antibody like cetuximab. I became curious if the anecdotal anti-cancer stories over the years were having trouble rising above the “only-anecdotal-noise” because attempting/monitoring the efficacy of beta-glucans had not been stratified to a patient population that was simultaneously taking an anti-cancer antibody (like cetuximab). Once again, thankfully a randomized clinical trial is in progress to test that scientific hypothesis – but unfortunately I was excluded from the trial and I literally may not have time to wait for the trial results…
The wheels of an annoyed (ok, possibly mad) scientific brain started to turn.
Are 1,3-beta glucan pills commercially available? Yes – check.
Are 1,3-beta glucan pills very safe to take? Yes – check. (Hippocrates gave a sigh of relief).
One of the big scientific questions remaining was: the beta-glucan clinical trial uses iv-dosing. Was there a big difference between iv-dosed beta-glucans versus taking pills? For many drugs there is a huge difference. In the case of beta-glucans: No (at least in rodents). In a number of scientific publications it has been shown that orally-dosed beta-glucans behave very similarly in terms of both immune effects and anti-cancer efficacy (when co-dosed with an anti-cancer antibody like cetuximab). A potential issue is that humans ≠ rodents so there is indeed still a possibility of a species difference. But at least it looked like there was a reasonable possibility that beta-glucan pills might show similar effects in humans as beta-glucans which are iv-dosed.
After seeing that the underlying scientific rationale was plausible, the chance of toxicity very low, the published equivalence of oral dosing in animals in terms of immune activation and anti-cancer efficacy (and my blockage from the clinical trial!) – as a very annoyed (ok, possibly mad) scientist, I decided to give a big proverbial middle finger to my clinical trial exclusions & I’m now actively taking 1,3-beta-glucan pills along with cetuximab as a single person (n=1), “self-directed clinical trial” (and yes, I am also eating a lot of mushrooms 😉 )
As a n=1 trial, I’ll never know if the beta-glucans I am taking helped, hurt or did absolutely nothing. If it sounds like I am using my body as a science experiment… well I am… but I’m a scientist and this is the most important research project of my life…
But the moral of the story is to illustrate the wild and unique world of being a Stage IV cancer patient. As long as you keep Hippocrates happy (do no harm!), keep your doctor informed & there exists a scientifically plausible possibility that doing something may help, you do it. You have nothing to lose and the potential upside is the biggest one possible. Life.
Oh yeah, the second moral of the story, hell hath no fury like an oncology scientist excluded from clinical trials 🙂