Eric von Hofe, cancer researcher and president of the biotech company Antigen Express talks about his article in the October issue of Scientific American called "A New Ally against Cancer," about cancer vaccines.
Steve: Welcome to the Scientific American podcast, Science Talk, posted on September 30th, 2011. I'm Steve Mirsky. This week on the podcast:
von Hofe: Sometimes after immunotherapy tumors, would actually appear to grow. But it turns out frequently what happens, you get immune cells coming into the tumor cells, so the growth is not due to the growth of tumor cells, but to the influx of immune cells.
Steve: That's Eric von Hofe, he's a cancer researcher and president of the biotech company, Antigen Express in Worcester, Massachusetts, and he's the author of an article in the October issue of the Scientific American called "A New Ally against Cancer" about cancer vaccines. We spoke recently when he was in New York City.
Steve: We go all the way back over a hundred years. You discuss in the article the work of Coley, who had some really interesting and creative ideas back then.
von Hofe: Right, right. He had noticed that in some cancer patients that had serious infection and high fever, that in those patients the cancer sometimes would regress. So people have noticed for a while that tumors were kind of like wounds that wouldn't heal. So what he did to induce this infection, kind of a mock infection, was take bacteria, heat them gently till they were dead, inactivated, but they still induced fever in patients who you inject them into. So he did this repeatedly, induced a very high fever, and sure enough in many of those patients, he got an efficacious response in the cancers. So again, an indication that he was stimulating something—of course, they were not very clear on the workings of the immune system—but something that could have a positive effect whereby the body on its own could then fight off the cancer.
Steve: In a situation like that, there are so many variables. Once you start inducing fevers you might have been involving heat shock proteins, who knows what was going on. But it did look an avenue to be pursued.
von Hofe: Exactly. And, in fact, that was used for, really, quite a while up until people really discovered radiation and chemotherapy. So chemotherapy was something that, you know, it was much more of a rational process, where people realized that DNA replication was important for the cancer; so okay get something that would poison the DNA, or the replication machinery and thereby those cells, particularly cancer cells that are rapidly dividing, would be preferentially killed.
Steve: And you don't pursue the possibility of the vaccine aspect because the others, the radiation and the chemo seem to be working in a really promising fashion, so the other things just gets put on the back burner so to speak.
von Hofe: Right. So at the time, you're right, they just didn't know enough about the immune system. Now it was clear pretty early on that a lot of these agents, they had a lot of nonspecific toxicity. So, you know, there have clearly been advances in the use of these more toxic agents. But people always, you know, they knew that the immune system was great at killing off lots of different things, very specifically with no side effects. So this was really, kind of, what people were hoping for to get this added specificity in cancer killing without the toxicity.
Steve: And your article also talks about Paul Ehrlich, who is, you know, one of the giants in the history of medicine and medical research and his efforts in this field.
von Hofe: Right, right. Well he was one of the first people that observed that, or proposed the immune surveillance, to think that there was something in the body that was on its own combating cancer; and didn't, you know, couldn't define what it was, but it was that idea that really planted the seed for what's later come to be known as the immune surveillance mechanism for reducing the incidence of cancer in people.
Steve: The idea being that cancers are constantly cropping up and constantly being swept out by the immune system.
von Hofe: Exactly, exactly. So, if you look at, you know, it's clear enough that if immunogenic events are generally required for cancer, so you could then estimate statistically the number of mutations that occur in a human body per year, and from that, get an idea the number of cancers that one might expect. But, in fact, thankfully that incidence of cancer was much lower than one would calculate; so to explain that discrepancy, people then came back to the immune surveillance therapy. There's got to be something that always on the prowl looking for something different and fighting off those early cancers so that they don't appear.
Steve: Let me go off on a mini-tangent, because a lot of our listeners probably have never even heard of Edward G. Robinson, but they should go see, it's probably on Netflix, go get Dr. Ehrlich's Magic Bullet and watch the movie with Edward G. Robinson—and Ruth Gordon, I think, plays his wife—and it's really a pretty decent biopic about this real medical colossus.
von Hofe: Yeah, good movie definitely, definitely yeah.
Steve: So, we've been relying on chemo and radiation, for the most part, for many decades. How is the idea of a vaccine against cancer coming back into vogue, and how does a cancer vaccine differ from a conventional vaccine?
von Hofe: Right. So people first had the idea of doing this—it really goes back many decades, I think 30-odd years ago, when I was in the graduate school—people had the idea of taking cancer cells,just radiating them and trying to immunize, say, animals in this case to see if they could have an effect. They didn't, the short of it was. I mean, there was some observation in animals that were interesting but nothing that ever made it in the clinic. So, it wasn't that people, that the idea fell from favor, they just didn't know how to do it. So it really took a lot of, you know, basic research, by a lot of different people to find out the different aspects of the immune system, how it worked and how one could then manipulate that, how one could present tumor-associated proteins, so called tumor antigens, in a way that you could stimulate the immune system to actually do its job in terms of killing off the cancer.
Steve: So, what specifically has gone on lately in the pipeline that makes people excited about the prospect of having actual therapies in clinicians' hands, you know, relatively soon?
von Hofe: So, About eight years ago, some studies were done that showed, kind of, a proof of principle. They activated the T cells from patients, stimulated those outside of the patient's body, reinfused those, and they showed they could do that in a manner that gave you an anticancer effect. So, that was really, kind of, a brute force mechanism. There were lots of other trials that people conducted during the last 10 years, which did not have positive outcomes, as they were used to looking for them. So, there were a number of reasons for that. Some, they just had not figured out the right way of delivering the antigen. But other things include not being able to know exactly what to look for. So, for instance, with the cytotoxic agents that everyone's familiar with, it's a fairly simple mechanism of action. You give the person cytotoxic agent, the tumor hopefully shrinks and that's a good thing and that helps relatively rapidly, so that's in a couple of weeks, you know, very quickly. With the immune system, that takes longer to stimulate, and what makes it pretty difficult is the idea of tolerance. So this is because cancer cells arise from a patient's own tissues, the immune system doesn't really like to go after them. Of course, if it did, there'd be a lot of autoimmunity, which is problematic. So this is known as tolerance, so one needs to break tolerance. To do that, one needs to figure out a way of ramping up the immune system with various agents, presenting the antigen in various contexts, to actually get a response that is effective. So, you know, you can't look immediately; it can take up to a year sometimes to get a sufficient response of the immune system to actually do something. Other things people have noticed is that sometimes, after immunotherapy, tumors would actually appear to grow; so initially people saw that, they were like, "Oh my God, this is terrible, we're doing the exact opposite." But it turns out frequently what happens, you get immune cells coming into the tumor cells, so the growth is not due to the growth of tumor cells, but to the influx of immune cells. So, these were things that, of course, people had to learn, and clearly the FDA had to be educated. They had to be convinced that this is going on, because they are the ones ultimately that are approving things. So there was a, you know, fair bit of learning that was done this last 10 years. The upshot of it is though, and there's been enough trials done, that people are starting to see these similarities in different things. So, in different types of treatment, people are seeing that the tumor looks like it's growing a little bit, so it's like, "Okay, you know, we're not crazy." On top of that, people are seeing interesting things, increased survival, things that don't quite make sense if you look at it in the light of classical chemotherapy. So in particular, what we were just talking about, sometimes the tumor can look like it's still growing, but there's an increase of survival, So, again this is something that is very contradictory for the FDA, and we really needed to learn how to use these agents. So I think there's been a lot of learning going on in the last 10 years. That, if you look at the field as a whole, you start seeing patterns, you clearly see that we are having an effect with immunotherapies and that's given lots of encouragement to people in the field.
Steve: And it's important that you have enough of these different trials—maybe they're even phase I trials—going on, so that you can start to see these things, so that you know that, as you talk about in the article, your benchmarks for success get redefined; not that we're defining them downward, we're just saying in this course different things happen that you have to watch out for, and they may mark the fact that you're actually getting something positive here.
von Hofe: That's absolutely right. That's absolutely right. So there was just, you said it exactly correctly. There were lots of trials done, and it was really after people started comparing notes and gathering enough data that we began to see these patterns and seeing that we really had something. So lot of people persevered a long time. I mean, our company, you know, the company was around since the late '90s. We started doing clinical trials in 2003, a lot of people were like, "Gosh, guys, you know, I don't know if this is going to work, there are too many questions here." So, but we persevered and along the way we started to see that we were having immunological response that we hoped to see with our compound, and at the same time, you know, the field was emerging. So, I think, you know, we're not alone in that. There are a lot of people in that position, so seeing that you're getting smarter as you're developing. And, of course, the person who's first obviously gets some of the biggest prize. So, in this case that was probably Dendreon, that was approved about a year ago. Again, this is a somewhat more complex type of immunotherapy. So, this is with the cells from the patients again that are stimulated and modified outside the body, reinfused in, but that actually made it past the finish line. They got approved by the FDA and that coincided with lots of other earlier phase results, phase II results; and people, sort of, compared notes with what they did to get over the finish line and could start to draw a line from where they were in their earlier trials and see a, kind of, a clear path forward. So that gave a lot of impetus to the field.
Steve: And again that's still the first and only FDA approved cancer vaccine therapy.
von Hofe: That's correct, that's correct. Now there was another agent recently approved Yervoy, Bristol-Myers Squibb, which modifies the immune system. Essentially what it does is it, kind of, takes the breaks off the immune system. We talked about the idea of tolerance, whereby the immune system doesn't like to go after its own tissues, cancer arises with normal tissues; of course that's part of that problem. But what Yervoy does is that it actually takes the breaks off the system and allows the immune system on its own to fight the cancer more effectively. So, while you're not activating the immune system in a way that you are with vaccine, clearly we're using knowledge that was gained during this last decade. So a lot of people point to that as part of this larger success in the field of immunotherapy.
Steve: And would you fear an autoimmune side effect problem with that kind of therapy?
von Hofe: One does see that occasionally. That happens; it's generally not very severe, although people do need to watch that, and there are medications that are available if needed; but that's clearly a problem because it's, again, it's not as specific as a therapeutic vaccine. It's a more general type of treatment, where you're taking the breaks off the immune system, but you're taking them off everywhere. So, to be absolutely clear and precise, it's not a vaccine. So, a vaccine is something where, ultimately people will probably find ways of combining these things where you take the breaks off a little bit, and then you give some specific stimulation against certain cancer-associated proteins, which is really more how the immune system works normally. Normally you're not taking the breaks off immune system. You get infected with a bacteria or virus or something, the immune system recognizes that as foreign and kills it effectively. So that's ultimately really what we're going after.
Steve: And the cancer vaccines, we have to think of them a little bit differently from vaccines that were used to like a flu shot, because you're not going to just vaccinate a population. These are for patients, it looks like, who already have cancer, but it's in a very early stage and it can recognize the cancer, that specific cancer, and keep it from growing rather than just let's get everybody to be on this and then nobody's going to get cancer.
von Hofe: Right, right. So, very definitely, the cancer vaccines are therapeutic vaccines. So they're not prophylactic like antiviral vaccines, flu vaccines and such. I mean, clearly, you know, so one has much more latitude obviously combating cancer in terms of toxicity because what we have so far is pretty tremendous, the cytotoxic agents, and it's pretty clear that with the vaccines so far, there is much less toxicity. So, over the past 10 years, again when one started to having do trials, in late-stage cancer patients, which is typically the population one uses, but as people advanced these trials, it was very clear to the FDA that there was minimal toxicity with these agents. So, particularly what we're developing peptide vaccines, modified peptide vaccines; you know, peptides are breakdown products of proteins in the body, so, there's really nothing foreign to the body whatsoever. And so, the FDA then came to a comfort level with toxicity of these agents and allowed them to be used in earlier-stage patients, which it looks like is probably the population that'll benefit the most. Now, clearly Dendreon was approved in later-stage prostate cancer patients. So I think people are hopeful that even in later-stage patients, one can get activity, but the thinking is you'll probably see your greatest activity in the earlier-stage cancer patients.
Steve: And what specifically is your company working on with the peptide vaccines?
von Hofe: Sure. Yes, so we have a slightly modified peptide; so the company has a technology platform, which aims at specifically stimulating CD4 T helper cells. So it's clear that this cell population is critical in generating a robust immune response against some novel agent. It's also important in overcoming that tolerance that we talked about. So what we've done, we took, first of all, a target which was known to be involved in the growth of the cancer, HER2, which is also the target of a monoclonal antibody out there, Herceptin. So, we didn't really take a chance on that; we knew that if we could have a positive impact in terms of generating response against HER2, we should be able to see some activity, because it was already validated in the clinic, thanks to Herceptin. So we started that project back in '05. We started the first clinical trials, showed that our peptide was safe and generated a specific, potent immune response. Based on those results, we started the phase II, and this is in breast cancer patients. The goal is to see a reduction in relapse in this group of cancer patients, the breast cancer patients. So, we're about three-quarters of the way through the study and have seen positive results so far. So, so far, we're encouraged by what we've seen, so it looks like we're indeed, we can tell we're generating a response against the HER2, and indeed we're getting indications of efficacy. So we're very encouraged by that.
Steve: And prevention of relapse is a reasonable thing to look at, because they're being treated presumably normally with the conventional armamentarium. So you're not going to be able to see whether you're doing something to destroy the tumor.
von Hofe: That's right. That's right. Now we're in a little bit of a fortunate position, in that, Herceptin initially—so this is the antibody that goes after HER2—that was initially approved in metastatic cancer patients, which is populace that the FDA likes to see things working in initially, and then it was approved in patients with earlier stage, so prevention of relapse, so not just overall survival, but prevention of relapse. So, we're fortunate we have that precedent. So, and that was another reason we went into this population. Because, you know, the thinking was that it would work better in earlier stage patients. But in some cancers you don't have an endpoint that the FDA will approve. They want survival. But in this instance of breast cancer, we did have that. So, that was the reason we went into this population with our initial vaccine compound, therapeutic vaccine.
Steve: So, other than because you can make money, why do this in the private sector rather than in an academic research setting?
von Hofe: Well, I mean, it's a good reason for biotech in general, is that you can, in fact, raise more money—although it's difficult these days—for doing clinical trials than you can in academia. Clearly, you can do trials in academia, but you're still frequently working in a microcosm. I mean, there are compounds that generally you take them to a certain stage, but then even going through a phase II trial, that could take several million dollars; people can and do get grants for doing this, I think. And then clearly, of course, in phase III you're doing your registration trials—that's extremely difficult for academia. People don't really think about doing that in academia. The big difference is in academia, people are doing, you know, really exploratory research. They're looking to advance knowledge, find a proof of concept; they're not really geared to thinking, "Okay, what exactly is this drug going to look like once it's on the market." In biotechnology, that's what people are looking at. They're going to see, "Okay, what is going to make this a drug at the end of the day." So there are other burdens they take on. So it's really seeing, you know, how many patients one needs, what the end points are. I mean, there are lots of lots of hurdles one needs to think about that I think people in academia probably try to, they shy away from a little bit because it is, you know, it's a much larger hurdle to leap, to line some things up for approval rather than an exploratory study that builds knowledge, basically.
Steve: What has to go right? What do you need to discover, what barriers do you need to overcome in the next few years for this kind of approach to actually get some footing?
von Hofe: Well, we've cleared a number of hurdles so far. I mean, the first is showing that we have biological activity, showing that we do not have any toxicity. The biggest next goal is really showing significant efficacy. So we have in our early data, we've shown that we have fewer relapses in our peptide vaccine arm, compared to the control arm of the trial. What we need to do is basically, you know, allow those data to mature; it just takes time, the trial has to run its course. We're hopeful then about a year from now, we should have those statistically significant data, such that we can go to an, it's called an end of phase II data with the FDA and then, march onto the phase III. So that's obviously a very big hurdle to clear and, you know, we'll probably not go that alone. That's something where with good phase II data, larger companies become interested. They see that it's not just science anymore, it's not just proving a hypothesis. We're showing that you actually have the data, that you're showing efficacy. Then it'll get interesting, and clearly at the end of the day, I mean, what's it's about is saving people's lives, and that's you know, that has value right there and people recognize that.
Steve: So, at some point, things go right enough so that a company that actually would be producing the drug gets involved and a partnership or a buy-out or something happens.
von Hofe: Well, it's not necessarily the company is producing the drug. It's a company that can codevelop; so first of all there's, you know, there are tens of millions of dollars for these phase III trials. And again it's also in these larger companies that have things like a sales force, distribution network, that we as a smaller biotech company do not have. So there's, you know, it's a marriage in that sense; in that we come with we know the drug, we know the history of it, we've laid out the tracks for the train to go down, but we know that around the corner, there's going to be things like distribution, sales all these things, which larger pharma is really, you know, better equipped to deal with than we are.
Steve: So then you're the organelle that gets absorbed into the cell.
von Hofe: Yeah, so to speak, so to speak; right exactly, exactly.
Steve: Well, obviously good luck. I'm sure everybody out there would be really delighted if we had some new weapons against cancer.
von Hofe: Absolutely. Thank you very much.
Steve: Sadly, the 1940 movie, Dr. Ehrlich's Magic Bullet, with Edward G. Robinson, does not, in fact, appear to be available through Netflix. So, I guess, just be on the lookout for it. Some movie channel has to run it one of these days. You'll find it really interesting.
That's it for this episode. Check out the cancer vaccine article in the October issue. And get your science news at our Web site, www.ScientificAmerican.com where you can check out our article on what physics luminaries think of the claim for faster-than-light neutrinos. And also bid farewell to the Tevatron, where they're turning off the lights. And follow us on Twitter, where you'll get a tweet each time a new article hits the Web site—our Twitter name is @sciam. For Science Talk, I'm Steve Mirsky. Thanks for clicking on us.