Chapter 1: Throwback
If you live in the US you have more than a 1 and 3 chance of developing cancer at some point in your life. So I want to start by asking, why do we get cancer? Why is it so common?
In high school, I was taught to ask by my science teachers not why, but how. But I think in this case, it makes sense to go back and try to understand why we get cancer and, in fact, go back all the way to the origins of life. So the fossil record tells us that from the time the Earth first formed several billion years ago, it took about half a billion years for the first cells to evolve. And from that point, it took a shocking three billion more years for multi-cellular organisms—animals and such—to evolve. Why did it take so long? It seems to me that it would be much more difficult to create a cell from scratch.
I suspect that one reason is that cells are fundamentally very selfish, and evolution had to figure out how to layer in many levels of control, to make sure that in a complicated animal, that the somatic tissues—the cells that comprise the vast majority of tissues in the body—serve the purposes of the germ line. But of course a very powerful selfish streak still lurks in every cell in the body. And this is fundamentally, I think, why we get cancer—because animals have a germ line that is shared with the somatic cells but is still different, and the somatic cells, as they divide they can accumulate mistakes.
Now to understand how a somatic cell might turn into cancer cell, we have to understand something about the genetic material itself. DNA is a beautiful double helix. Human DNA is composed of about six billion nucleotides. The nucleotides are the rungs on this ladder, and they are read out as a code that produces or encodes all of the molecules, the complicated tissues, and components of the body. As each cell divides, those six billion nucleotides must be copied, and as they are copied errors occur. It's estimated for human cells that the error rate is about 10 to several hundred mutations per cell division per cell. That may sound like a lot but remember it's in the context of six billion nucleotides. So it's actually a very small error rate, but it adds up over the course of a lifetime.
As mutations accumulate through aging and cell division, and through exposure to carcinogens, there's the possibility that some of these mutations inactivate growth control mechanisms that are involved in controlling normal cell division. In fact, with new ultra-high throughput DNA sequencing technologies, we can now get a very clear view of the mutations that are present in tumor cells and it turns out that there are thousands—sometimes tens of thousands—of mutations present in the genomes of these cancer cells.
So an analogy can be made between a cancer cell and a pathogen or a parasite. So for instance, an infection, a bacterial infection typically starts with maybe a single organism but rapidly can develop into an infection where there are billions of microorganisms that have invaded the body.
Tumor cells are in a sense much the same. A single cell, in principle, can give rise to a large clone ultimately of billions of cells. Of course with growth, whether it's bacteria or cancer, with growth comes the possibility of heterogeneity, because as each cell divides, as we’ve learned, mutations occur and accumulate, and that gives you the possibility, if you are a microorganism or a cancer, that gives you the possibility to develop resistance to whatever therapy that's being applied and we'll come back to that a little bit later.
Now there's a critical difference between a parasite and a tumor cell, and that is that parasites don't have a human genome whereas tumor cells do. And that creates an enormous challenge, because any cancer therapy has to distinguish tumor cells from normal cells. And even though many mutations accumulate in a tumor cell, compared to the total number of nucleotides it's still a tiny, tiny percentage. So, if you compare my genome, for instance, to yours there is one difference per thousand nucleotides or bases. If I had a tumor, the difference between a typical cell in that tumor and my germ line would be fewer than one mutation per hundred thousand nucleotides. It's also worth putting that in the context of what's happening in our normal tissues.
As we age the tissues in our bodies accumulate mutations. So by the time someone is in his or her mid-50's, there are nearly as many somatic mutations in a normal tissue as there are in a tumor cell, at least in the case of tissues that have to be repaired frequently like the lining of the gut, like the skin, like the blood cells. Of course, in healthy tissues those mutations don't do any harm. In tumor cells, through a process of random mutation and natural selection, certain functions, as we talked about, have been inactivated or activated leading to malignant growth.
In the case of a parasite, it's relatively simple for the body itself to distinguish, and of course that's what the immune system does when it reacts to a parasite infection, a pathogenic infection. Cancer is much more challenging as we've heard, because there are relatively small differences that the immune system has to detect.
So I want to turn now to try to understand why the war on cancer has been so much tougher than we thought it would be.
Chapter 2: In Search of Magic Bullets
Over a century ago, Paul Ehrlich worked on the concept of a magic bullet, which is the idea that you could create a therapy that would perfectly distinguish a disease cell from a normal cell. The idea being that you could find some function—some molecular structure or behavior —that was unique or at least preferentially found in the diseased cells and largely absent from normal tissues. And of course, this idea ultimately gave rise, in the case of pathogens, to antibiotics. Now in the case of cancer, this is considerably more difficult because cancer cells don't have a unique genome that differs greatly from the normal genome, from the germ line, whereas pathogens, of course, do.
So the challenge was, "How can I find a specific function to target?" This proved to be very difficult, and around 1950, two Nobel Prize-winning scientists, George Hitchings and Gertrude Elion, began to try a different approach, which was to target proliferating cells using agents that are often called "cytotoxics." These are agents that interfere with fundamental functions in cells such as DNA replication. And therefore, they have a preferential effect on dividing cells. Because tumor cells, of course, divide, they target tumor cells, but also many normal tissues divide. And so as a result they give rise to a myriad of very difficult side effects that we know as the toxicities associated with many cancer therapeutics.
The magic bullet postulated by Paul Ehrlich has been difficult to find, but in the last couple of decades, there are a few examples of these. One of the best known involves chronic myeloid leukemia, also known as CML, and the target Abelson kinase. Abelson kinase is largely non-essential in adult cells. And CML cells become dependent on its function—presumably serendipitously. And that gives the opportunity to create a drug, which targets CML cells quite specifically, and is comparatively benign against normal cells.
But even if you have a magic bullet, there are other problems that can confront you. And one of them is drug resistance.
By the time a tumor is detected in the body, there are generally billions of cells, and recall that we talked about how dividing cells accumulate mutations at a rate of ten or more per cell division. So spread among those billion cells are, we expect, billions of mutations, and of course the human genome is a few billion, six billion nucleotides in length. So that means that there is a very high probability that every nucleotide in the genome has been altered in at least one cell somewhere in the tumor. So assuming you can gain resistance by a single genetic change, there is a very high probability that that change already exists, and by the process of natural selection—selection enforced by treatment with the cancer drug—resistant cells will emerge. There's another problem that we have to think about when we're confronting cancer therapy. To a somewhat surprising extent, tumor cells—at least initially—cooperate with a therapeutic intervention in that they can commit a kind of cellular suicide called apoptosis, whereby when stressed or subjected to some therapeutic intervention, they actually disintegrate, fall on their swords, and kill themselves.
But as they accumulate mutations—as they continue to evolve and develop resistance to therapeutic intervention—they become more like a pathogen, a bacterium, or even something like yeast—single-celled organisms that don't commit programmed cell death. But of course the immune system evolved to deal with such entities. And so for over a century, the goal for scientists has been to try to engage the immune system against cancer.
Chapter 3: The New Immunotherapy
As cancer cells evolve, mutate, and are selected in the body, they behave more like a parasite, like a bacterium or like yeast. A pathogen like a bacterium can infect the human body and give rise to many cells that cause disease, just like a cancer cell can give rise to many cells that trigger a disease.
When we treat pathogens, we have the benefit typically of an immune response against the parasite, and we supplement that with agents, antivirals or antibiotics.
So why not engage the body's immune defenses against cancer? In fact, over the many decades, efforts to develop immunotherapeutic agents that activate or engage the immune system against cancer have been tried, but with quite limited success.
It has been clear that the immune system does see something in a cancer, because you often find in tumors signs of inflammation—sometimes infiltration by immune cells, lymphocytes and so forth. So the question has been, what is being recognized by the immune system and can we get the immune system to recognize more things or recognize them better—without of course unleashing the immune system on all our normal tissues. That is, can we develop agents that are more like magic bullets and less like the chemotherapeutics, the cytotoxic drugs that were developed starting around 1950?
So I'd like to now introduce some concepts for immunotherapy that have developed over the last few years. The first one is the idea of a BiTE® or a Bi-Specific T-Cell Engager.
BiTE is a genetically engineered antibody construct that is made by linking the targeting regions from two different antibodies. One region binds to a protein found on killer T cells—the most powerful type of immune cell—while the other is designed to engage a tumor-selective target. The key idea here is to find a protein target that predominates on tumor cells but is rare on normal cells. The goal is to use the BiTE molecule to link the T cell and tumor cell together, at which point the T cell should recognize the tumor cell and initiate mechanisms to kill it.
The second concept I'd like to discuss involves the use of a virus, not as an enemy as we've talked about, but rather as a friend—a tool against cancer. This approach employs modified viruses that can kill tumor cells when injected into cancer lesions, and also make proteins that summon immune cells to the tumor, where they find debris that includes a range of tumor-specific antigens. One goal is to have the immune system learn to target tumor cells in parts of the body that have not been injected with virus.
The final concept that I'd like to talk about involves a discovery made a couple of decades ago that T-Cells not only react to a stimulus—like a pathogen —but also have a machinery to quiet them back down. And this makes sense so that they don't react overzealously to normal tissues and create a dangerous situation during an infection. So these mechanisms are called checkpoints. There are now molecules that have come forward into the clinic and have shown that by inhibiting these checkpoints with therapeutics, one can reawaken the T cells in some cases in a very specific way and a very powerful and effective way against tumors.
And so these approaches that I've just described, as well as some others that I haven't had time to mention, have very great promise in the context of treating cancer …
Now we're in a position to bring in the very selective and powerful arm of the immune response against cancer. And by having a combination of those two mechanisms, those that are aimed at the tumor cell itself and the immune response which acts in a mechanistically much different way, we now have the opportunity to treat cancer with combination therapies that should enable us to deal much more effectively with the very significant problem of drug resistance.
So the immune system has the weapons to kill tumor cells that are resistant to cancer therapies, including chemotherapies. It's taken a very long time to unlock the secrets of how to harness this power. And we're really right in the beginning stages of understanding this and bringing the force of the immune system to bear against cancer. But I've gone from being a pessimist about treating cancer because of all the inherent difficulties that we've talked about, to being an optimist about the prospects for the future. I think it's not unrealistic to anticipate that we can reproduce in cancer some of the same successes that we've enjoyed in our fight against parasites and other pathogens.
Amgen's head of Discovery Research, Alexander Kamb, discusses his view on why we get cancer, what makes it so difficult to treat, and why immunotherapeutic approaches look so promising.
In 1971, the United States launched a war on cancer with the enactment of the National Cancer Act, laying the groundwork for cures by investing vast amounts of time and money into research. Four decades and tens of billions of dollars later, the death rate from cancer has diminished ...but only slightly.
Today, new tools are helping untangle the web that makes cancer such a formidable enemy and, in the process, providing insights that suggest future victories may be won by devising treatments that help the body’s immune system target tumors.
Why is cancer the ultimate parasite?
Why do we get cancer? The answer goes back to a battle that is as old as life itself.
In Search of Magic Bullets
How far has treatment come?
The history of cancer research has revolved around finding ways to target tumor cells while minimizing damage to healthy tissue.
The New Immunotherapy
Where is science taking us?
New approaches to cancer immunotherapy are starting to show that it’s possible to enlist the body’s immune response to fight tumors.
The scientific ideas and opinions expressed in this presentation are those of Dr. Alexander Kamb and do not necessarily reflect the views of Amgen as a company.