Doug Williams: Taming the toxicity of cancer drugs

Doug Williams, Image Courtesy of Lonza

This episode is sponsored by Lonza. Click here to listen to the full podcast episode

Sally: So far we’ve learned that exosomes are tiny packets of information produced by cells and released into the blood stream that allow cells from different parts of the body to communicate with one another.

Each individual exosome contains a little bit of the cell’s cytoplasm wrapped up in a specially labelled bit of membrane that provide the directions for where the exosome should go and which cells in the body should absorb it. It’s a nifty bit of biological engineering; a natural postal system for the body.

This has brought many researchers to the same question: can we take what we know about how exosomes naturally behave, and use it to either diagnose diseases from a simple blood test, or to treat diseases by creating a highly sophisticated method for delivering drugs.

To find out more, I spoke with Dr Doug Williams, the president and CEO of Codiak Biosciences. Codiak is a pharmaceutical company focussing on using exosomes to treat disease, whose exosome manufacturing facility was recently acquired by Lonza. I asked Doug, what was it about exosomes that got him interested enough to start a company…

Doug: The company got started to focus on trying to take these naturally occurring small particles that cells release, that they use to communicate with each other, and to figure out a way to harness that system to use it as a drug delivery vehicle. So how can we take a naturally occurring, naturally evolved system in the body that's used for cells to talk to each other and figure out a way to put the messages inside those exosomes and get them delivered to where we want them?

Sally: It's essentially like a postal system. They're putting things in envelopes and sending them off to different parts of the body to where the cells themselves can't move. How did someone think, "I know, I can hijack this system and use it to either diagnose or treat disease?"

Doug: Well, the diagnosis part is actually probably a little better established. But what people have come to realise over many, many years now, is that the contents of the exosome both on the surface, but also inside, is almost a reflection of the cellular state at the moment that the exosomes get released. They capture a little bit of cytoplasm and nucleic acid, and as they're gobbling up the intracellular contents, that sort of tips off what's going on inside the cell.

Sally: So you mentioned it can reflect the state of that parent cell. What sort of things can you tell about the cell just by looking at the exosome?

Doug: One is in cancer diagnosis, because there's nucleic acids that get packaged up inside the exosomes. The idea is that you can sequence the nucleic acid inside the exosome and find mutated oncogenes, for instance, and some of the other bad actors that are associated with cancer.

Sally: Is the cancer cell deliberately putting those nucleic acids into the exosome to spread them, or is it just a byproduct of there being so many of them floating around in the cytoplasm that some of them happen to have got bundled up at the same time.

Doug: Yeah, I think in this case it's an accidental incorporation of cellular contents, sort of an accidental packaging and release into the bloodstream. And it makes it a very easy way to detect and identify these mutated transcripts.

Doug: The other application I've seen that's particularly interesting, I think, is in Alzheimer's disease. Probably a decade or more now ago it was discovered that a protein called tau, which is one of the proteins that aggregates in the brain in Alzheimer's patients, that you could pick that up in the blood of patients much earlier than the time at which they developed signs and symptoms of Alzheimer's.

Sally: And as a patient, what is it like to have this diagnosis using exosomes. So how would we have diagnosed it before we had exosome therapy? And then what does it look like now? Presumably, especially if you're looking at things in the brain, it's better than having a needle stuck in your brain. Is that the alternative?

Doug: I think that's probably a true statement. The alternative probably would be to sample your cerebrospinal fluid, which is also pretty invasive and something that not a lot of people are going to sign up for. So taking a blood sample is sort of no big deal. Isolating the exosomes is actually fairly straightforward. And now that we've got the tools to be able to do very sensitive sequencing, both at the protein and the nucleic acid level, it's actually quite straightforward from a diagnostic perspective.

Sally: That's incredible. How long does it take to do one of these diagnoses in the lab?

Doug: Depends on the assay you're using, but from the time the sample comes, it can be done in a day.

Sally: Wow. That is incredible. And presumably it's only getting faster and cheaper as with everything in genetics.

Doug: That's true.

Sally: Now, moving on to the treatment side of things, because this is really where your company is focusing. And as you were saying, the therapeutic side has been around for a while. You described how you are able to use these cell communication packages. How does that work?

Doug: The trick was to be able to find a way to molecularly manipulate what gets incorporated into the exosome. And we discovered two proteins, which exosomes have on their surface, that had never before been reported as part of the biosynthetic process for exosomes.

Doug: And they turned out to be pretty abundant. So we are now able to use those two proteins as scaffolds, essentially, to display things very precisely.

Sally: And what sort of things are communicated by the surface? Because in my head, following this letter analogy, it's just telling the exosome where to go and when to be absorbed its recipient. Is there more to it than that?

Doug: There's a lot more to it. I think the proteins on the surface of the exosome control everything from which cell type they're going to go to and be taken up by, to... some of the proteins can actually signal the target cell directly.

Sally: So it calls ahead of time of being delivered.

Doug: Yeah. "Hey, I'm here," sort of thing.

Doug: There's also proteins that seem to control the rate of uptake across the membrane. And then what happens once these particles get inside a cell to allow them to unpackage their contents.

Sally: So I'm imagining the outside is really the drug delivery side. Whereas the inside is the actual drug that you want.

Doug: It's a little more complicated than that. In some cases, the conversation takes place outside the cell. And then in the case of things like nucleic acids or other molecules, it's more common for those to be inside the exosome because they want to cross the membrane and get unpackaged inside the cell where the target for those molecules actually resides.

Sally: And this is all so much more refined than just putting the drug directly in the bloodstream and having it floating around with no messenger system at all.

Doug: Well there's a fundamental concept in drug development called the 'therapeutic index', which is the desire to get more of your drug, where you want it and less of your drug to those places that cause toxicity and the wider you can make that window the better off you're gonna be and the greater your likelihood of success.

Doug: And that's one things that we focus on a lot with the exosomes that we engineer and build and produce for therapeutic purposes. We really want to get every bit of efficacy out of the molecule that we can and try to avoid as much toxicity as possible. I mean, that's a quality of life issue for patients who are on our therapeutics.

Sally: I mean, we've mentioned cancer already, but thinking of something like chemotherapy, which famously takes such a toll on the body.

Sally: So where are these therapeutics? Are they just in the lab in research stages? Are any of them being used? Can you give me a rundown of what sort of diseases we are already treating and what sort are in the pipeline?

Doug: Sure. So we're actually, I think, the first company to take engineered exosomes into the clinic. And we have two programmes right now, both in immuno-oncology that are enrolling patients in clinical trials,

Sally: Immuno-oncology. Is that cancers of the immune system?

Doug: No, actually it is using the immune system to eliminate cancer.

Sally: To fight cancer, okay. So which cancers are you targeting?

Doug: We've got one programme that's focussed on cutaneous T-cell lymphoma (CTCL), which is a disease of malignant T-cells in the skin. So you can actually see the lesions and it provides a fairly straightforward way of assessing whether your drug is working or not. You can literally watch it happen on the arms and the back and the legs of these patients with that disease.

Sally: How long does it take to see effects?

Doug: For the same molecule in a different format in that disease; typically in about six to eight weeks, you'd start to see responses taking place in the skin. So it's pretty quick.

Doug: The molecule that we're working on for CTCL never became a drug because it's too toxic with systemic exposure. It's a perfect illustration of this therapeutic index concept that I mentioned earlier. We're actually injecting the drug directly into the lesion and because it's associated with an exosome, it actually stays there. And so we get all of the drug effects locally.

Doug: In the healthy volunteer study that we did with that drug candidate, you couldn't see any systemic exposure to the drug molecule and no tolerability issues as a result of that.

Sally: Were they just injecting the drug straight into the tumour before and just hoping that it wouldn't get carried around the body?

Doug: Yeah. And unfortunately the unmodified cytokine didn't stay in the tumour. So you got systemic exposure. You got all of the side effects that really prevented it from becoming a drug.

Doug: Even though we know it's active in a number of different diseases, the inability to control the toxicity was the Achilles heel for that particular pathway. So we think we've fixed that with attaching that molecule to the surface of an exosome, putting it right in the tumour and showing so far, in the studies we've done, that there is no systemic exposure to the drug. So we've apparently tamed the tox and hopefully retained all of the good, beneficial aspects. There's a number of other diseases where activity had been seen in the past, but because of the toxicity never made it across the finish line.

Sally: Please tell me you've got a t-shirt that says "I tamed the tox" on it.

Doug: I'll send you one.

Sally: I'm just imagining there must be hundreds of drugs that have been tested in test tubes in tumours in a Petri dish that we know that they will successfully kill it. But that as soon as we give them to humans, it's just too reactive. So we almost don't need to discover new drugs. We can go in our back catalogue and work out ones that we haven't been able to use up to now.

Doug: Yeah, that's certainly one approach and it's an approach that we're taking.

Doug: The other is pathways where we know they're important pathways but we haven't been able to deliver the drugs with any degree of specificity to the right cell type. Our programme that will enter the clinic later this year is one that targets a transcription factor and transcription factors actually control networks of genes.

Doug: The one that we're interested in is called STAT6 and the exosome that we've built allows us to target a very specific population of macrophages in the tumour itself. And when that happens, those macrophages go from being immunosuppressive to being immune-stimulatory. And you see an anti-tumour effect as a result of that.

Sally: So you inject it, it changes how the tumour acts, and so now the tumour's just screaming out to the natural immune system, "I'm a cancer. You're probably gonna want to kill me soon."

Doug: It's actually an indirect effect. The macrophages go from saying, "Yo, T-cells stay away", to basically inviting them into the tumour.

Doug: And the reason this is such an important therapeutic approach is again, we've altered the surface of the exosome using engineering. What we've done allows for incredibly specific delivery of our therapeutic candidate to the precise population of cells, in this case in the liver cancers that we're gonna be treating, to allow for this switch in the macrophage behaviour to facilitate an immune response against the tumour.

Doug: So targeting the drug to exactly the cell type you want it to go to with systemic administration. That's what we're doing with what is now going to be our third therapeutic candidate into the clinic later this year.

Sally: That's incredible. What is the dream for you with exosome therapy? What's the big goal that you are reaching to achieve?

Doug: It's always about developing therapeutics that have an impact on patients' lives. I mean, the whole point of doing this is to create a steady stream of drugs that are gonna be transformational, starting out in cancer, but there's so many different applications to this technology.

Doug: It is a brand new technology area. A new platform, which I think has enormous possibilities across a whole spectrum of therapeutic areas. We're immunologists, most of us in the company, so we've focused on immune-mediated targeting and immune-mediated diseases and treatments. But I think that's really just the tip of the iceberg in terms of how this platform can be used in different therapeutic areas.

Doug: So more to do, but in six years, we've come a long way from a standing start.

Thanks to Doug Williams from Codiak Biosciences, though I will say, I’m still waiting for my “I tamed the tox” T-shirt to arrive in the mail!