A Trip Inside the Science of Cancer
Now we're getting somewhere!
Few types of biotech companies capture the hearts of biotech investors like companies working on treatments for cancer. Virtually everyone has been touched by the disease - either personally or via a close friend or family member. We all root for a "cure" to the disease, and are attracted to investing in the sector like moths to a flame.
The latest revolution in cancer treatment is the concept of personalized therapy. Those familiar with the sector might smirk at me calling personalized therapy "the latest revolution", but I'm sticking by my guns here. If you attended the most recent ASCO meeting, you understand how the idea of targeted therapy has captured the minds of oncologists. And what is targeted therapy but a way to personalize therapy for a particular person's cancer? (Those going to the Minyans in the Mountain event will hear me touch on this. In writing this article, I'm hoping I can skim this subject matter in my short presentation and move more quickly into how this impacts biotech investing.)
It is impossible to accurately assess the promise of the newest generation of cancer drugs without understanding how cancer works. This article is designed to give the reader a basic primer on cancer biology and immunology.
The Human Immune System
You have cancerous cells in your body right now. What keeps you from developing tumors is your immune system. One way of looking at cancer is a disease caused by the immune system's failure. There are two key kinds of critters in your body that help keep you cancer free.
The first is a T-cell. This class of cells is responsible for killing abnormal cells before they can multiply and do any harm. For the real science geeks among the Minyan readership, cancer researchers are especially interested in CD4+ and CD8+ T-cells as they seem to do the bulk of the work of fighting cancer.
The other is a class of cells called antigen presenting cells. T-cells are stupid. They have little idea what to attack. Antigen presenting cells - particularly dendritic cells - are the cells in the body that identify something that doesn't belong. They then rush back to where naive T-cells are hanging out and teach the T-cells how to recognize what to attack. Those T-cells then go out and do the dirty work.
The body communicates with proteins. An antigen is a protein. Antigen presenting cells go by and sample the proteins churned to the surface by cells in the body. When they recognize an antigen that doesn't belong, they grab that antigen from the cell and use it to train the T-cells. When the T-cells rush out to do their business, they are looking for cells displaying that specific antigen. When they find one, they kill the cell.
We now understand all (or nearly all) cancers have one or more antigens that make them distinctive from healthy cells. Much of the work now being done in the treatment of cancer revolves around identifying these unique antigens and constructing drugs that make use of the fact these antigens only exist on tumor cells. These unique antigens are, therefore, the basis of targeted cancer therapies.
Unfortunately, finding a unique antigen target is very difficult. The perfect antigen target is always found on all tumors and never found in healthy tissue. There are few, if any of these perfect antigens that we can target drugs to. So what cancer researchers have done is create a trade-off.
One example of this is Genentech's (NYSE:DNA) Herceptin, a targeted therapy currently approved for the treatment of breast cancer. This drug targets an antigen named her2-neu. This antigen is not found in most normal healthy tissue, which is good. Unfortunately, only 25% of breast cancers are marked by her2-neu.
An example going the other direction is an antigen called Lewis-y. Several companies, including Seattle Genetics (NASD:SGEN) have targeted therapies to this antigen. Lewis-y is seen in a high percentage of multiple types of cancer. Unfortunately, it is also found in the lining of the digestive system. A common side effect of drugs targeted to Lewis-y, therefore, are digestive system problems like ulcers and perforations. While drugs targeting Lewis-y can still be successful (Seattle Genetics' SGN-15 has shown good data in early trials against lung cancer), you will have more side effects with this drug than with other antigen targets.
So it is a balancing act. Most antigens seen in a great many tumors are also seen in healthy tissues. Antigens rarely or never seen in healthy tissues usually are found in a limited number of cancers. Thankfully, this balancing act is increasingly tilted in cancer patients' favor. Advancements in lab technique and equipment are making it more likely we'll find targets that resemble our "perfect antigen".
The Wily Tumor
So we've found our perfect antigen. Now we're all set to cure cancer, right? Nope.
Tumors have an amazing ability to evade detection. Remember, their ability to evade the immune system is what allowed them to take hold in the first place. They are quintessential Darwinists, changing their appearance in a desperate attempt to stay ahead of the immune system. Evil buggers, these tumors.
Understand what is happening inside the body. Your immune system has to walk a fine line between not attacking normal cells ("self" cells) and attacking what it perceives as abnormal cells ("non-self" cells). If the immune system begins attacking self-cells, you get autoimmune diseases like lupus and rheumatoid arthritis. There are dozens of checks and balances in place to make sure the body doesn't attack cells it is not supposed to.
Cancer is comprised of the body's own cells. What makes them cancerous is they are replicating madly, not performing the functions they should, and taking up resources from surrounding healthy tissue. Because they are essentially self-cells, cancer tumor antigens are often recognized as self. Therefore, when the antigen presenting cell "reads" the antigen it sees nothing amiss and wanders off to the next cell. No immune response is generated and the cancerous cells are left to their own nefarious devices. This is called "immune tolerance"
I use the term "disease Darwinism" often when talking about cancer. In the normal course of cell division, things get out of hand. Cells that would become cancerous grow and are eliminated by the immune system because either they are recognized straight away or they grow to a size that they begin to get "complaints" from neighboring cells. These complaints are answered by the immune system, which promptly kills the offending cells.
For reasons that are not altogether known, sometimes the natural system hiccups. Let's look at the following system:
Here we have a bunch of normal cells (N) and a few tumor cells (T). The immune system has been used to mopping up the tumor cells for some time, and has become efficient at it.
However, if you look closer at the tumor cells you'll notice they are not exactly the same. While all are cancerous, two of them are slightly different variants (T1s versus T2s). This tosses a variable into the mix that the immune system is not used to handling. It might have been used to seeing T1s but it has no idea how to deal with T2s because it does not recognize them as something bad. After the immune system makes its pass, we're left with this:
The T1 tumor cells are removed but the T2 cells remain. Tumor cell genetics are inherently instable. In this case, that instability created a genetic abnormality that the immune system could not handle. Now we have a problem. The tumor has gained a foothold.
We noted previously, however, the immune system would respond to complaints from neighboring cells when the tumor cells got too big. Why wouldn't this same process cause the immune system to also adapt and recognize T2 tumor cells? That's a good question and one of the least understood parts of cancer.
Evasion by Chemical Warfare
Cancer cells will secrete certain chemicals whose net effect is to weaken the immune system response. In the graphic below, you can see this as our established tumor sends out chemicals (C) to intercept immune system cells (I).
In some cases, the chemicals repel the immune system cells. This usually happens to antigen presenting cells (APCs) who are trying to learn how to kill the tumor. In most cases, these chemicals simply weaken either the APCs or T-cells so much they are ineffective.
Breaking Immune Tolerance is Key
Almost all targeted cancer therapies make use of the immune system somehow. Monoclonal antibodies like Herceptin, Rituxan, Erbitux, and Avastin use the B-cell side of the immune system as a targeting mechanism. Most other targeted therapies make use of the T-cell side of the system, somehow working through the body's antigen presenting cell mechanism. Many of the latest monoclonal antibodies make use of the T-cell system, too.
The core goal of any of these therapies is to create an immune reaction where there was once none. These therapies - and this is key - must not only cause the immune system to recognize and react according to the training they provide, they must also break the cycle of immune tolerance to disease cells already inside the body.
We read all the time about new therapies that create a robust immune response against the desired target antigen. This is a good first step, but it is essentially meaningless on its own. Just because a therapy creates an immune response to a target antigen does not mean an immune response will be created against a patient's disease.
Let's return to our old nemesis, the T2 tumor cell, adding some detail to the cell this time to explain this crucial point:
In this graphic, our T2 tumor cell is marked by the antigens A1001A and A0110A. A company does research into a particular line of cancer, and discovers that 25% these cancers express the A0110A tumor antigen. Then they create a therapy that encourages the immune system to attack A0110A.
When they get to Phase I trials, they inject the patient with their drug. The first thing they do after making sure the patient isn't about to die is take a blood draw to see what the dendritic cells and T-cells are up to. The results are fantastic in that they are creating a robust T-cell immune response to A0110A, the target antigen for their therapy.
But wait... Here's what is actually going on inside the patient:
The immune system is broadly mobilized with immune system cells (I) targeting A0110A, but the majority of tumor cells are expressing A1001A. There's no significant match. Despite the fact the drug created a fantastic T-cell response (look at all those (I)mmune system cells trained to do battle with A0110A (T)umor cells!), they were not able to break immune tolerance to the patient's cancer because the antigen target was chosen badly.
When a company developing a cancer immunotherapy has a drug that fails in clinical trials, it is usually because they were unable to break immune tolerance. If a company were able to create an immune response to the A1001A (T)umor cells, they are far more likely (but not guaranteed) to be successful. This is why choosing the proper target antigen is so important.
It is admittedly unusual these days for a company to get all the way to human trials and miss as completely as indicated by our example. If this kind of miss happens these days it is usually because the company was pushing a science beyond its limits for marketing purposes. The broken wreckage of past failed dendritic cell clinical trials are piled high, however, so this is not a trivial concern.
A characteristic of advanced cancer is a great deal of mutation. After battling the immune system for quite some time, cancer cells begin to look less and less like each other. This is the root of a systemic roadblock to developing approvable therapies utilizing the immune system. The longer a tumor grows, the more genetic mutations will occur. In advanced disease, our collection of tumor cells may look like this:
The cancer still has T2/A1001A elements in it so any screening test for that antigen prior to therapy would be positive. However, a significant number of tumor cells simply do not have the target antigen.
Cancer immunotherapy is essentially the art of convincing the patient's immune system to break immune tolerance against tumors. There are an increasing number of companies who are working on this method of treating cancer.
Early attempts at cancer immunotherapy failed primarily because they were tested in patients with advanced disease. As the graphic above shows, advanced disease is less likely to have target antigen in any significant quantity. This makes targeted therapy very difficult.
Now that companies have learned this lesson, they are testing in patients with less serious disease and are having much better success. Some on Wall Street see this as a negative for this technology ("it only works on healthy patients"). Since most immunotherapy has few side effects, it's perfect for "healthy patients." Let chemotherapy purveyors fight over the "sickest" patients.
Some believe immunotherapy will work in the sickest patients if you use a piece of the patient's tumor or "banked" tumor cells as the antigen source. Banked cells are tumors that were removed from anonymous patients years ago and kept alive in a lab for scientific research
The claimed advantage from using tumor cells as a key ingredient is the ability to capture multiple antigens. For example, if we have a tumor that looks like the one in the graphic above with a ton of different antigens, logically you want some way to be able to train the immune system for them all. You'd then generate an immune response that looks like this:
While this sounds good, there is a problem: Success for these types of drugs is all about quantity of dendritic cells you can train. Most processes are able to return about 10 million antigen presenting cells to the patient - a level that seems to be something of a threshold for effectiveness when targeting a single antigen. If those 10 million cells are split up among a bunch of different antigens, then is the threshold for effectiveness still reached?
Also, what's to guarantee the bit of tumor you've harvested is representative of the entire disease state? A corollary issue is whether the antigen profile of the trained dendritic cells is similar to the profile of the tumor. In the example above, the T2/A1001A tumor type makes up 33% of the tumor. How can we ensure that 33% of the antigen presenting cells reinfused into the patient are trained for T2/A1001A? We don't mean to suggest strict equivalence in numbers is required, but there has to be some relationship otherwise the therapy will simply accelerate the Darwinian self-election process, leaving the natural Darwinism of the tumor cells we discussed earlier which will simply self-select for the less targeted tumor types undisturbed.
If you're still with me, congratulations. This "science stuff" is why investing in biotechnology stocks can be so hard. A little mistake here or there in interpreting scientific data can ruin your whole day.
Despite the length of this article, I actually left out quite a bit. I didn't touch on the complications surrounding the HLA system, which adversely affects anyone using banked tumor cells. I also left out two or three important ways tumors evade the immune system.
What I hope I've accomplished is to give insights into the concept of targeted therapy, especially as it relates to mobilizing the immune system to fight cancer. More and more new drugs do this, so it is important for you to understand what these companies are talking about when they throw around words like "antigen" and "immune response."
More generally, I hope I've shed some light on how science is important to choosing the right companies for your investment dollars. A key characteristic of our company's research is the integration and description of the science for the benefit of our subscribers (in fact, this article is a summary of our March and April issues that reviewed companies working on dendritic cell therapies).
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