(2 of 4) In our second conversation, Dr. Kornguth introduces paraneoplasia, a syndrome in which antibodies associated with a cancer cause a compromise in function in a non-related system. He uses an example of visual deficits experienced by some patients with early-stage small cell carcinoma of the lung to highlight the cost-benefit ratio weighs the positive features gained by a patient’s survival and wellness with the adverse consequences of treatment. Small cell carcinoma of the lung patients that present with the visual deficits of paraneoplasia tend to have longer survival rates than those who do not. Thus, the research shows that the same process that impairs one function extends life. He recounts his experience in the 1970s and 1980s researching paraneoplasia and connects this work to emerging treatments in cancer immunotherapy.
Lancet article (1985): Autoimmune Basis for Visual Paraneoplastic Syndrome in Patients with Small-Cell Carcinoma of the Lung
National Cancer Institute: Immunotherapy to Treat Cancer
Society for Immunotherapy of Cancer: Immunotherapy
Karen French: We're back again with Dr. Steven Kornguth. We're talking about paraneoplasia as an autoimmune disease, Lessons Learned From Basic Research. Steve when we spoke last time you talked about autoimmune diseases such as "those in which a compromise in function is caused by the patient's own immune system". What is paraneoplasia? And, how is it an autoimmune disease?
Steve Kornguth: Thank you very much, Karen. So, paraneoplasia is a dysfunction or a disease seen in cancer patients, which has an autoimmune basis. What's happening is that the patient with the tumor begins to produce antibodies reactive with the tumor. These antibodies from the tumor, recognize not only tumor material, typically proteins and sugar proteins, but they also recognize a normal protein in another organ system such as: the retina, the brain, the cerebellum, the thyroid gland, ovary, and peripheral nervous system.
These antibodies are recognizing structural features in both the tumor material and in the normal organ.
What the antibodies are doing in the normal organ for instance the retina, they are affecting negatively the function of that other organ. So for instance, if it's a target in the eye there is seen visual dysfunction, visual disorder as an optimalogical problem. If the cerebellum then there is a gait or self orientation space phenomenon.
What the antibodies are doing is reacting both with tumor and with the target organ namely the retina. The good news is that these antibodies are slowing down typically the rate of growth of the tumor cell by ablating them or somehow negatively affecting their function. The other side of the coin, the negative, is that the antibodies are ablating or killing the normal nerve cells which is showing up in the patient as a very noticeable difficulty. So, for example, in patients with small cell carcinoma of the lung they may appear to have lost central vision or peripheral vision and they come in with a complaint that they can't see well.
As a physician examines them, they see that there is a loss of vision in the central eye visual field, its called a central scotoma.
And now from the data we understand with paraneoplasia. It's associated, in some cases, with small cell carcinoma of the lung.
This gives us an ability to begin to diagnose the small cell carcinoma. Because the visual change appears earlier than the clinical signs of the cancer.
There's another condition called melanoma, another kind of a cancer, early symptoms of that patient appear as night blindness in these patient's you can detect antibodies reactive with a different cell in the retina. Not the large ganglion cell, but the bipolar cell and we know that bipolar cells in the retina control night blindness like conditions.
So we have two different phenomena of eye problems scotoma or night blindness that give rise to a potential coexisting condition called the cancers.
And the early detection of this can lead to treatment of the tumors primarily but also for diagnosis of the patient and for development of therapies that may be useful in the management of the patients disease. All of which relate to sense making. There is a clinical appearance of something that doesn't look like the cancer because there's no cancer invading these organs, that were talking about. It's a remote effect of the cancer on the body generating antibodies which then react with the central nervous system in the cases I've been interested in.
Karen: When someone has paraneoplasia, they walk in and they say I can't see and the doctor says we need to check to see if you have lung cancer. What?
Steve: Yes so actually ... there's a more critical element before that. So the physician looking at the patient with the eye problem. He will not or she will not, the physician that is, say you have lung cancer because critical is what is the past medical history of that patient.
The symptom of visual loss in the eye is most frequently some eye problem. That is, it's not a remote affect.
Almost ... the overwhelming majority of times there's something locally in the eye that's causing the visual loss.
When you do a past medical history, so the patient says I've been smoking cigarettes every day. I'm a 72 year old man. I've been smoking since I'm 15 years old, a pack a day. The first question now is, well, I'm going to look first in your eye and try and discern is there something going on locally that I can understand. And, if I don't see anything some lesion of the eye, impact injury, or tumor growth in the eye then I have to ask: Is there something else that can explain the phenomenon?
So I look at your chart. I see your heavy smoker. We know there's an association between heavy smoking and small cell carcinoma of the lung.
Now I begin to say well, you know, as the patient walks and I think it would be helpful to have a detailed X-ray and examination of your lung to see if there is something going on there.
Not saying this lung cancer because until you have the validation that there is something there, to inform the patient they have lung cancer is inappropriate.
So... And the same thing with the melanoma story you try and understand always locally what can explain the phenomenon that I'm seeing clinically.
If I can't do it from a local thing that I have to ask is their a remote cause of the visual dysfunction that you're having.
Karen: So when there's not a local explanation, then you go in and then say it could be something else?
Steve: Exactly rights! This is sense making. So the sense making combines the clinical presentation with laboratory data, with past medical history, and with the genetics of the person involved, family history that is.
Karen: But once all gf that comes together and they do all of that, the fact that those connections are there makes paraneoplasia fascinating.
Steve: Yes it does.
Karen: That's a very interesting story. So how did you get into that story? That's the question.
Steve: Well, because of significant family history of cancer, I've been interested in cancer issues diagnosis and treatment for many years. In the 1960s, I had the notion that one could take tumor cells or tumors inject it into an animal and generate antibodies to those specific tumors. With the hope that the antibodies could kill the tumor because at that time, 1960, we didn't have a way of making antibodies to a single target.
It turned out that the experiments we did were not particularly productive. We got antibodies. We had antibodies produced, but they didn't react solely with a cancer cell that we were concerned with.
By the 70s Milstein had developed a way to produce antibodies that react only with a single region on a target. Those were called monoclonal antibodies.
So in Madison, Wisconsin, we had a very excellent research team that looked at visual function in cats and other animals.
And the work at Harvard with Wiesel on defining motion detecting cells in the retina, which were large cells and target detecting cells in the retina again by the Harvard group, Torsten Wiesel.
Gave us the question: Could we produce antibodies selectively that would ablate either the large cell or the small cell.I had good technologies that we developed in our laboratory to isolate large cells in general. So we isolated large retinal ganglion cells from cow eyes. I was in Madison, Wisconsin and Oscar Meyer was there so we had an abundance of retinal cells from cow eyes. Together with Larry Kahan at the University of Wisconsin, we produced high titer monoclonal antibodies reactive only with a large retinal ganglion cells.
In experiments with Peter Spear, who is a physiologist looking at motion-detecting cells in cat retina, we used these monoclonal antibodies to ablate the large retinal ganglion cells of the cat eye. So, they lost the ability to detect motion, but they could detect targets and this is important because I believe that there were diseases where you would have the same manifestations.
Anything that you can do in a laboratory I believe is going to be seen in some clinical disorder in the human.
And so, we were able to demonstrate the ablation of the large retinal ganglion cells in the cat eye using only monoclonal antibodies that reacted against a large retinal ganglion cells from cow eyes.
I went to a great colleague, Ron Klein in Ophthalmology department at Wisconsin, and ask him do we have any patients which have essentially a sudden loss of vision?
And this could be explained by a loss of large retinal ganglion cells that is motion-detecting ones and preservation of others.
So Ron, with his major insights into visual disorders said "As a matter fact, we have 2 patients currently in house that have a central scotoma," loss of vision in the central visual field, "and it'll be interesting to see because they have no other pathology we can see by external examination in the eye." Whether there is some correlation of an autoimmune process, a process where the body is producing antibodies to something that cross-react with the large ganglion cells in the human eye.
And so I obtained blood from these patients. They were explained, of course, what's the study, what was going on and it was all informed consent. We found that the serum from these patients reacted with large retinal ganglion cells sections in the tissue section in a histology preparation. They did not react with a small or medium sized ganglion cells in the retina. So we had the model of how the animal studies starting with bovin large retinal ganglion cells, demonstrated in cat eyes in the laboratory now has translational implications.From how a patient, who is presenting with visual disorders can cause the same sort of problem.
These patients were both very heavy smokers, and a correlation in patients with smoking is small cell carcinoma of the lung. That's a frequent occurrence. These patients came in without a diagnosis of small cell carcinoma of the lung. So the presenting sign was a visual loss.
But it was due to a remote effect namely the presence of the small cell carcinoma eliciting immune response to the tumor where the antibodies to the tumor cross react with the ganglion cells in the retina.
Causing the early sign to the patient, a visual loss that promoted them coming into the doctor.
Karen: So when they went into the ophthalmologist, at the beginning, to both of them, he just said "I am not sure what's wrong with you. I'll keep testing."
Steve: Well he mapped the visual field loss. That was the first thing. Took the medical history and found that they were heavy smokers.
Karen: That was the one thing they had in common.
Steve: That was the one thing they had in common.
Steve: And they had these antibodies to the large retinal ganglion cells in common also.
Steve: So, the smoking, in common, for long periods of time the visual loss,number two
Steve: The fact that they had both had antibodies to the large retinal ganglion cells and the absence of ability to see some other cause locally in the eye. Gave us the notion of a paraneoplasia in these patients.
Karen: And those two were diagnosed with small cell carcinoma...
Karen: It presented itself
Steven: Well they did x-rays studies
Karen: They started coughing and it became obvious.
Steve: Thats right. So, the good news is you can use the visual function loss as an early diagnostic if you have also a clinical history of smoking and no local change in the eye that is apparent from the simple examination of the retina. And then you do a serum study and you find the antibodies and the smoking and you correlate all of these. This is sense making classically from a clinical point of view. I have the data from environment, from the history of the person, from the toxins that have been exposed to, prior exposures, and I can now make a diagnosis.
How do I treat that patient knowing it's an immune disorder? In several ways, I can do that. One: I can excise the tumor. Does the visual decrease stabilize? Yes, it does. Just by removal of tumor. Or, I can remove the antibodies.There is a technique we call the plasmapheresis, we remove the antibodies. Again, the visual deterioration stabilizes
Karen: So that's what you found...
Steve: So that's what we found this, that's right. Because you can do the diagnosis, you can treat early. You have the known methods that you can manage a patient with and the question is does it ... abated the disease? Does is it mitigate the progression of the disease? The answer is yes and all of those.
So that was exciting to me.
Karen: So what did you do next?
Steve: We then became interested in a variety of other autoimmune diseases that are paraneoplastic in origin. And so we studied patients who have melanoma but where the early diagnosis was night blindness.
So, we obtained from Joel Weinstein serum from the patients with melanoma and demonstrated that they had antibodies that reacted with what are called the bipolar cells in the retina. These are cells involved in night blindness or night vision and the antibodies negatively affected the function of those bipolar cells.
And so we now have two different disorders small cell carcinoma of the lung, lung cancer. Melanoma, a second, where different protein antigens in the tumor evoke an immune response and this immune response changes the function of the retinal ganglion cells, so you can detect motion or of the bipolar cells which affect night vision.
And then to make it even more interesting another... and this was done in the 1970s and 80s. In our laboratories. Another colleague at Wisconsin, Art Polands, was also interested in paraneoplasia and discovered that some of the antibodies in the small cell carcinoma of the lung patient react with a different cell in the retina, the photoreceptor cells.
And, he discovered that the protein in the photoreceptor cells called recoverin is a target of some of these patients antibodies.
What this points out is you can have more than one antibody in a given tumor population affecting two different cell populations, either the retinal ganglion cell or the photoreceptor cell. With different locations but with a common presentation namely loss of vision.
So, what one has to do is to find what is the target organ of the antibody, because, what in the end I'm trying to do is improve the treatment and management and detection of the tumor in that individual. Each one of these different strategies will have the different treatment protocol.
Karen: The goal of management is?
Steve: Decreasing the dysfunction that the patient has, the blindness, number one. Increasing the life, namely determining what is causing the antibody production. Is it a tumor? If it's a tumor, excise the tumor. Reduce the antibody production in those patients. However, you have a double-edged sword here, right? Because the same antibodies that are causing the visual dysfunction are controlling the
growth of the tumor itself.
Steve: So, the patients with a small cell carcinoma of the lung and the visual loss tend to live significantly longer than patients with small cell carcinoma of lung without the visual paraneoplasia. So the antibodies have been doing two things increasing survival time of the patient, but causing neural damage and visual loss.
Karen: Does it slow the growth of the tumor?
Steve: The patients live longer with a paraneoplasia than those without the paraneoplasia event. They both have small cell carcinoma of the lung.
Karen: It's not that they detect it sooner, its that they...
Steve: No, they actually live longer
Karen: They slow the growth of the tumor
Steve: That's right. So, the antibodies are killing the tumor. So the question is can you develop antibodies which are selectively killing the tumor cells but not causing the visual dysfunction. WE'll talk about that later.
Steve: If you want some of the emerging technologies that are coming from that
Karen: Okay, so we are now in the 1980's
Steve: 1980s, 1990s, yes.
Karen: So, what next? What came after that?
Steve: We had discovered that you had these paraneoplasias and that you have the clinical histories that you can correlate with what's causing the loss of function and what are the targets of the antibodies produced against that. So there's a new technology today, essentially, which is leading to immuno ablation.
Karen: Immuno ablation? Help me understand what immune ablation means.
Steve: Immuno implies the immune system, and ablate means to kill or remove or destroy.
Steve: So from the studies I have been telling you about, until this point, it turns out antibodies against neuronal populations or tumor populations can kill the target organs or the tumors.
We have two great scientist at the University of Texas, George Giorgiou and Brent Iverson, and their work has been aimed at increasing the affinity, the binding ability of antibodies, to target antigens. Typically, you have whats called a dissociation constant between the antibody and the target antigen, of 10 to the minus 6. So that's where half of the antibodies bound to the material and half of it is not. They have...
Karen: And the work is happening now?
Steve: developed a way to take antibodies that are...
Karen: And is that immunotherapy?
Steve: against the particular antigen and increase the binding so that it's 10 to the - 15th.
Karen: Its getting exciting.
Steve: That means you have to get all the way down to that level before you see the dissociation from the target.
They have developed this with funding in the biological defense program by preparing antibodies against Anthrax toxin.
Imagine now,that you can take the antibody producing cells from the patient with paraneoplasia. And generate very high affinity binding of the antibody selectively for the tumor cell that does not cause the blindness in the patient.
Karen: That would be nice.
Steve: That would be great because it would be a major advance in the ability to treat these specific cancers using cells generated from the patients with the selective monoclonal type antibodies against the tumor, but that do not cross react with the retinal ganglion cells or with a bipolar cells or with a photoreceptor cells. That would be the challenge.
Karen: The next 10 years should be pretty exciting.
Steve: It should be very exciting.
Karen: And it all started with eyeballs
Steve: It started with eyeballs.
Karen: Thank you for today.
Steve: Thank you.
Karen: This was great