What’s your degree?
Edward Greeno: MD
What type of doctor should we call you? Oncologist?
Edward Greeno: Yes I’m a medical oncologist. I do primarily gastrointestinal (GI) oncology
Tell me a little about salmonella and what it is, and why most people don’t want anything to do with it.
Edward Greeno: Salmonella is a gram negative bacteria, it’s a bacteria that often causes food borne illness, it’s actually the source of some pretty severe illnesses in a fair number of people. And it’s something that’s been around obviously for a long time, it’s also something that can infect people without making them real sick sometimes. And one of its properties that’s important to us is that it’s natural behavior when you get infected with it is that it infects the G.I tract, that’s the bowels, and spreads into the lymphoid tissue and then spreads into the liver and spleen which are essentially part of the immune system in the gut. Those are also all places that cancers in the G.I tract like to spread; the regional lymph nodes and into the liver, and so this bacteria already goes to the places that we are trying to treat cancers of the G.I tract.
I read that you saw a study from Austria that this might indeed be useful for cancer but it might also could kill you.
Edward Greeno: Right, it’s been recognized for a long long time that occasionally cancer patients would get infected with something and their cancer would get better, and so about 150 years ago people started deliberately trying to do this. Now they weren’t doing this with salmonella at that point, we’re not quite sure what bacteria they were using, probably some form of strep and other things. They would deliberately infect a patient or their tumor with bacteria and it would sometimes produce very dramatic responses but in an era where you couldn’t really control the bacteria, you didn’t have antibiotics or any other way really to understand what you were doing, this frequently ended up killing the patient. Over the years people have progressed to using what amounted to vaccines using killed bacteria as a way to induce some sort of intense immune response to attack the tumor, that’s what has led to a lot of interest in using the immune system to attack cancers. None of that has worked out very well except for some special circumstances so for the most part it has not yet been successful. In the last couple of decades though as we’re gotten to the point where we can manipulate microorganisms a lot better, using infectious agents either viruses or bacteria as a way to treat cancer, has become much more common, because we can do so many things to change the virus or the bacteria’s behavior to make it safer and more effective.
This is an early; you’re not in phase 3, so you started this here?
Edward Greeno: Yes, I started the clinical trial here, just in the last year, the actual development of this though was very long. One of my colleagues, Dr. Dan Saltzman, is the one who actually developed the salmonella, came up with this idea originally, so he spent about 15 years, breeding the salmonella that we are using now, treating mice and looking at how it works in the laboratory to help understand what we were doing with it and why it would work in human tumors
And it was working in mice right?
Edward Greeno: It works quite well in mice, so his very first model was in mice giving them a, using a cell line of colon cancer cells, giving them liver metastasis and treating them with the salmonella
And what did it show?
Edward Greeno: And in that case you could see very dramatic shrinkage of the metastasis in the liver of these mice without making them sick. Through a series of experiments he was able to show the salmonella made interleukin-2 (IL2) which is one of the genes we put into it and the salmonella would go to the cancer, grow in the cancer, the mice would have an immune response against the cancer and that would reduce the volume of cancer in these mice. And the surprising thing was how well you could do that without making the mice sick. So the bacteria that he created is attenuated, that means it’s been weakened and it doesn’t make people sick and it’s important because there have been a lot of attempts as to weaken it in a way that doesn’t get rid of its ability to attack the cancer, so this particular strain still will grow inside of tumor cells. The bacteria actually doesn’t just grow inside your body it actually gets inside the individual cells so that it’s right there inside of the tumor cells, and this strain of bacteria is just like a strain that might be used as vaccination against salmonella, so it’s something that will infect you without making you sick, but in addition to the attenuation, the weakening process he put into it a gene for interleukin 2 . So interleukin 2 is one of the regulators of your immune system, that’s probably one of the key ones, we use it clinically sometimes, directly interleukin 2 is a treatment for some kind of cancers. We cangive very high doses which make people very sick, in a few cancers like melanoma you can see very dramatic responses, but it comes at the expense of great toxicity and it doesn’t work for a lot of types of cancers, so here by putting the gene for interleukin 2 into the salmonella, the salmonella is growing inside the tumor so a tiny bit of interleukin 2 produced by the salmonella represents a pretty high concentration right in the vicinity of the tumor, and it attracts the immune system to attack the tumor.
So you want both?
Edward Greeno: You want both.
Salmonella might have worked alone but you want to make it even more effective
Edward Greeno: Yes, in his early experiments in the mice it looks like the IL2 is important for its function. In some circumstances it doesn’t make as much difference, but in most circumstances you get a much more potent anti-cancer effect by putting the interleukin 2 in.
What type of patients are candidates in your research?
Edward Greeno: This study it’s really open to people with just about any type of cancer. Because this is such an early study we are taking people who don’t have other treatments available to them and really the only requirement is that the cancer be growing in their liver so we can see if it’s having an effect on their scans.
So somebody who has colon cancer and it spreads they might be getting even more powerful effect than somebody let’s say with lung cancer, is that accurate to say?
Edward Greeno: That part I guess I don’t know, we know that it’s going to go to the G.I tract into the liver it may end up in the blood stream and get to tumors other places, we haven’t really explored that a great length. Other researchers with similar bacteria have given it intravenously. There’s a way to make sure it goes wherever the cancer is in the body and it tends to home to the cancer cells. The problem with giving it intravenously is you make, even when you weaken the bacteria, you make people very sick with the bacteria by giving it intravenously
So how is it delivered?
Edward Greeno: orally, so it’s very simple we have a little vial of the bacteria that’ diluted in some saline or some Gatorade, just a little shot glass the patient drinks it down and that’s all there is to it.
So the patients, even after you explain it to them, they must be squeamish about this
Edward Greeno: Yeah I mean, you tell somebody you’re going to have them drink salmonella nobody gets real excited about that. On the other hand most of these patients we’re already put through lot to treat their cancer I haven’t obviously tasted this myself but patients tell me it doesn’t taste bad, so it just tastes like the saline that it’s in so it’s a little salty.
And is it a one time?
Edward Greeno: yes, right now it’s a onetime dose; that’s part of the requirements that were put on us as part of the study, we first need to treat a number of patients with a single dose just to make sure it’s safe, and that’s the usual nature of these sort of early phase studies. We’re starting at very low doses and work our way up gradually and even though we are pretty sure based on all the animal studies we did that this was very safe and it’s not going to cause problems, You never know until you’re treating real patients with it, and so we are very cautious starting at doses that we’re sure aren’t going to make them sick and gradually working up to the full dose.
So where are you now?
Edward Greeno: So we’re about halfway through the study, the phase one, we’ve treated about a dozen patients and we are now at what we think should be the therapeutic dose so we’re just starting to treat people now with that will amount to essentially the full dose.
What have you seen so far in patients?
Edward Greeno: So far it’s expected, because we’re giving such low doses we haven’t seen any major changes we, as part of the study look at a lot of measures of their immune function and we’ve seen some minor changes, not enough to be clear if it’s the effect of what we are giving them or not so for the most part we haven’t seen anything, which in some ways is a success, the goal of this part of the study is just to make sure we aren’t going to make people sick and in that sense we’ve succeeded because we didn’t make anybody sick
Are we 2 years away or 6 months away?
Edward Greeno: So we’ll finish up on the phase one within the next 6 months and we’re in the process of writing the next phase 2 study and working on getting funding for that. So the phase 2 study we’ll be more specific, limited to more particular tumor types and circumstances so we can get a better sense of where and when we should be using it that study will allow us to use multiple doses. So that’s something that, our timelines always are longer than we expect but that’s something we expect to be up and running with the next year or so.
Are you the only one that you know of studying this?
Edward Greeno: There’s lots of other people looking at using salmonella to treat cancer, so the particular salmonella that we are using here, we’re the only ones doing that, we developed it here, and the only one I know of using salmonella with interleukin 2. But people are using other strains of salmonella that make a variety of other substances, the strategies can range from what we are doing, we’re trying to induce an immune response with the salmonella. You can also put genes for other things that might activate certain drugs so for example you could give a patient a pro drug, something that’s not activated against cancer, put a gene in the salmonella that would activate that drug and then you selectively activate the drug just where the salmonella is in the tumor. There’s a whole bunch of different strategies you could take so as a principle, I’m as much interested in the idea that we can get this salmonella to grow inside of human tumors and do something even if this particular strategy doesn’t work, it opens the door to a whole host of different ways of approaching it.
What do you think this will offer patients?
Edward Greeno: So I think probably for the patient population we’re studying now, people with very advanced cancers, the best we are really going to be able to hope for is to see it provide yet another tool that we have to help control the cancer, probably people with advanced cancer it’s not going to be something that makes it go away, we always hope for that and if that happened it would be great. But if it’s working in that setting, then we have the opportunity in using it in less advanced disease, earlier in the course of a patient’s disease where we might have a chance of actually eradicating small volume disease we couldn’t otherwise get rid of. It may also turn out that it’s very effective in some tumor types we don’t have other good treatments for, so things like, some pediatric tumor types it looks like it might be very effective. So once we get past the initial phase that it’s safe and we see some activity in some human tumors, that opens the door to exploring a whole host of particular tumor types that might work, and a whole host of different circumstances that it might work in.
So the door still seems to be open as to which types of cancer
Edward Greeno: So we started with this because that’s where the salmonella naturally goes, it seems like it’s most obviously going to work, but it’s not limited to that. Really that will be part of the work down the road, to figure out if it actually goes other places.
So where do you think this is going to go?
Edward Greeno: So we wouldn’t be studying it if we didn’t think ultimately it could turn out to be useful in treating human cancers. The reality is we always think that of things we study. We don’t pursue things that we don’t believe are going to work and many times things that are in this early phase turn out not to work no matter how well they worked in mice. We all joke that we’d like to be mouse oncologists instead of human oncologists because they seem to be a lot easier to cure. So I’m certainly quite hopeful that this is going to turn into something that will come into regular clinical use as a valuable agent but the reality is, many of the things we study don’t pan out, and we’re still a long way off from being able to say this is actually going to be an effective treatment and in real patients.
Are there other bacteria like salmonella that are being studied?
Edward Greeno: There are several other bacteria being studied, one strategy has been to use anaerobes, bacteria that like to grow in areas with low oxygen, because many tumors have poor blood supply and they have a low oxygen level and you can get the bacteria to grow quite well inside of a tumor that has a poor blood supply. That was done for example with clostridia, which is something that can make you very sick if you have a systemic infection, it’s very good at killing the inside of a tumor but doesn’t get the part that’s well vascularized. There’s one large study in breast cancer that was trying to prevent recurrences using a bacteria called corynobacterium which is something that doesn’t make people sick and often lives on your skin, that didn’t seem to pan out. There are bacterias that are like the bacteria in yogurt that tend to like to go to tumor cells as well. So all of these different ones are being explored now, and it’s an area, if you look at the number of papers published on using bacteria, a decade ago there was just a handful and in the last couple of years there’s starting to be more and more, because we really have the tools now to start manipulating bacteria and make them do the things that we want them to do.
This reminds me of using leeches and maggots to treat ailments, bacteria have been around for millions of years and seems sort of like an "old school" way to treat cancer, what do you think about that?
Edward Greeno: It is in some ways taking advantage of what people have recognized in nature, so as I alluded to before the earliest recognition of this was people spontaneously getting their tumor infected and their tumors getting better. So we always want to pay attention to those kinds of things that happen. The trick is so you notice that some people get their tumors infected, you can’t just start infecting everybody with bacteria and hope that it turns out well because usually it’s going to turn out badly, which was the case when people first started doing this. It really requires a lot of careful planning and study to be able to take something like that and turn it into a useful treatment. In fact many of the treatments we have started out that way, they started out as a natural herb or whatever but it’s only after careful thought about how it works and working through ways to make sure you know what you’re doing that we get to a point where we can actually rely on it as routine medical therapy.
If you could offer this as an alternative to chemotherapy, what would that do for patient care?
Edward Greeno: So anytime we have a treatment that’s less toxic and is effective, that’s going to be preferred, I suspect we will not end up in a position where this replaces chemo or radiation or traditional therapies, this will be just another tool in our toolkit that we can use to try and treat patients and our treatments don’t need to make people sick necessarily to work, some of them do and we have trouble getting around that, but many of our treatments right now, your statement that chemo makes people sick is true sometimes but actually many of our treatments that are very effective against cancer don’t make people sick so in that regard I don’t view this as replacing chemo or replacing something else it’s just yet another treatment, and I don’t really think of this as different kind of treatment, it’s just another medical therapy that happens to be a bacteria but we are studying it the same way we would a drug or radiation or anything else.
Tell me a little about Fred, did he have any effect from the trial?
Edward Greeno: So as best we can tell the salmonella that we gave him didn’t do anything to his tumor, and fortunately he’s continued to do well for now he’s been through lots of treatments in the past which it helped him for a while but as is often the case eventually they all stop working.
He said that his last scan was good though
Edward Greeno: yeah, he’s fortunate that his cancer is growing relatively slowly, for right now it’s not causing him any problems, as you saw when you met him, right now he’s enjoying himself and feeling pretty good and doing the things he wants to be doing.
He really has a good outlook on life.
Edward Greeno: One of the advantages of my job, as hard as it is dealing with patients with bad diseases is that there are plenty of people like Mr. Oakden who have such a positive attitude, it’s a pleasure to take care of him, even if I didn’t get rid of his cancer for him, taking care of him was a pleasure, because he really does have such a positive attitude.Is there anything else you’d like to add?
Edward Greeno: No I mean the things I always like to stress it’s easy for me, and those of us involve in these studies, to get really excited about it because they are exciting, we have to be cautious that doesn’t translate into people thinking this is going to cure everybody’s cancer next week, because it’s not. And I think the other thing is to recognize often the story sounds very simple, we thought about doing salmonella, we did a little genetic manipulation and we’re giving it to patients, it’s really important to recognize that it was 15 years of hard work on the part of Dr. Saltsman just to get to the point of starting to actually treat patients and it’s going to be a number of more years before we even figure out, is it useful or not in real patients.
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