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[Colin Miller] 

Hello, I'm Colin Miller, CEO at the Bracken Group, and this is Fractals: Life Science Conversations. Bracken is the professional services firm for life sciences and digital health organizations. Our intelligence ecosystem fulfils consulting, regulatory, marketing and analytics needs with an integrated and strategic approach.

Today's episode will focus on innovation in biological imaging and its role in cancer therapy, particularly in assessing treatment effectiveness in immuno-oncology. To explore this topic, I'm thrilled to be joined by Dr. Ben Larimer, a scientist, entrepreneur and president and CEO of CytoSite Biopharma. Ben has dedicated his career to developing novel imaging agents for cancer diagnosis and therapy monitoring.

As a co-discoverer of CytoSite's lead technology, he played a pivotal role in guiding it through successful first-in-human trials. Under his leadership, CytoSite has expanded its pipeline to include additional clinical stage molecules, with a particular focus on granzyme B PET imaging, an approach that could revolutionize how we assess immune response in cancer patients. Ben's journey started with a PhD in biochemistry from the University of Missouri, followed by a postdoctoral research at Massachusetts General Hospital.

Ben then established his own research laboratory at the University of Alabama, Birmingham, where he advanced his work in molecular imaging. Ben's contributions to the field have earned him several prestigious honors, including the NIH Director's New Innovation Award, the Hal O'Brien Rising Star Award, and recognition as the one to watch by the Society of Nuclear Medicine. Ben, welcome to Fractals, and thanks for joining me today.

[Ben Larimer]
Thanks for having me, Colin. That was an incredible introduction, and I feel a little embarrassed by it, but happy to be here. This is my first podcast, so, looking forward to having a conversation.

[Colin Miller]
Excellent. Well, I'm delighted to have you here, partly because not only with that background, you and I have collaborated and worked together over a number of years, but just because you are one of the leading experts in this field, and it's just a delight to be able to pick your brains, hear a little bit more, and understand where the programs are going, but also the thought of how the research is going and where this will grow to. 

[Ben Larimer]
The only reason why I'm a leader in this field is because I'm not afraid to jump in early and saw some of the amazing work coming out of MGH about a decade ago, and had a hunch that this was going to change the way cancer was treated.

[Colin Miller]
So, when you think of the building block approach, I think some of us think of Granzyme B, for example, as being a destruction part of that program. Perhaps to start off with, for those people who are listening who don't know anything about Granzyme B, perhaps you could talk about what Granzyme B is and just put it into context, and then we'll talk on how you think about that in the building or destruction process of pulling things together. So yeah, tell us about Granzyme B and how we should think about it.

[Ben Larimer]
Yeah, so Granzyme B is aptly named. It's an enzyme, meaning it's a protein that carries out some function. When you look at them under a microscope, they look like granules of sand.

So it's an enzyme in a granule, so it's a Granzyme. B is just, you know, there are a series of Granzymes, A, B. So Granzyme B is this enzyme, and it's found in the granules of your immune cells. Its function is it basically cuts proteins, and it cuts specific proteins.

Your immune cells use it when they find something that is foreign to you or otherwise flagged by your body as being harmful. These immune cells go to the foreign thing and release this Granzyme B, and the Granzyme B goes in and kills the infected cell or the cell that your body says is not supposed to be there. And it's an extremely potent molecule for getting rid of things that are foreign to your body.

As a protease, I like to think of it as like a little Pac-Man that goes along and chews up proteins that have a specific sequence to them. We were able to build on the back of some really great researchers and build a molecule that basically locks in the mouth of that Pac-Man and kind of acts as like really sticky peanut butter. We can get into that mouth, stick there, and then send out signals saying, hey, there's Granzyme B here, the immune system is active, and it's killing.

[Colin Miller]
Wow. Okay. That is quite the storyline.

How did you get from understanding Granzyme B, and what was it that made you suddenly go, I wonder if we can put something in there with peanut butter, as it were, and glue it in that allow us to image it? Why not the cells? And how does that then relate to cancer and those components

[Ben Larimer]
Cancer is obviously your cells going haywire, and we're always being exposed to things that can potentially make the cells in our body grow and grow out of control. And for the most part, part of what your immune system does is it surveils your body and it gets rid of these cancer cells. But in the cases where people develop tumors and malignant cancer, for one reason or the other, the immune system is no longer able to recognize cancer as being foreign and kill it.

People have tried for a long time, with vaccines and other things, to get your immune system to work, to kill cancer. But it had kind of fallen off in the wayside for a long time. A bunch of different researchers at the same time, well, for many years, had figured out one of the ways that cancer evaded your immune system and was able to grow was to use these proteins that they called checkpoints.

And these checkpoints would, even if the immune system got there, these checkpoints would act as brakes. They would turn off the immune system. So you'd have your immune system there saying, ah, this is cancer, we need to kill it.

But these checkpoints were basically saying, nope, sorry, can't kill us. People made drugs called checkpoint inhibitors that blocked the brake. Now the checkpoints were no longer able to stop the immune system and the immune system could come in and kill cancer.

These clinical trials started reading out about 2014 and the results were incredible. Some patients, when these checkpoint inhibitors were used, you were seeing in metastatic melanoma and metastatic stage four melanoma that had a 5% five-year survival rate, you were seeing these durable remissions of up to 10 years, which was just incredible. The problem was that some people got this amazing response, but most people actually didn't.

And we had no idea, we still don't fully understand why some people do and some people don't. And to make things even worse, the usual ways that we monitor response to cancer, like anatomic imaging to see the size of cancer, or measuring the amount of sugar, that cancer loves sugar, so measuring the amount of sugar that cancer eats, it didn't work with immunotherapy. Everyone kind of identified that, my gosh, we need some new way to monitor because we're treating people and some people are going to get benefit, but most people aren't.

And these drugs, you know, taking the brakes off your immune system, they could cause very severe side effects. So, we and others started looking at, okay, what could a biomarker be of immune response? The first thing was, oh, if immune cells are there, you know, that should be a good sign. What we kept seeing was that wasn't enough.

Immune cells needed to be there. So, it was necessary, but it wasn't sufficient. And Granzyme B had been an immunology marker for decades as a marker of immune activation.

But the canonical way of thinking about doing molecular imaging was you had to build, you had to target something that was attached to the outside of a cell. And Granzyme B is a little Pac-Man that's held in the granules and then released. And Eric and I came up with the structure of a molecule that would bind to Granzyme B. And we put it into our mouse models.

And I still have a picture on my phone. We did the first mouse imaging, and I was expecting to see nothing and prove them wrong. You can't image this secreted Granzyme B, even if it is the perfect biomarker.

And we got the first mouse scans popped up, and I could see some of the mice responded and some of the mice didn't. So, it was perfect. Just like a human, just like human immunotherapy.

And sure enough, you know, I was looking at four mice, and one of them had just, was just glowing with PET signal and presumably Granzyme B, and one didn't. And I took a picture of it, and I sent it to Eric. And I was like, I can't believe this worked.

And, you know, we were off to the races from there, expanding, repeating it multiple times, and looking at a bunch of different mouse models and conditions and things like that. 

[Colin Miller]
Unbelievable. Wow.

I've often wondered how that came about, because, you know, like you, it's, you're expecting to find a receptor, and to not go for a receptor attached to a cell was such a breakthrough in a lot of ways. You know, kudos to you and the team for actually pulling that off and making it work. 

[Ben Larimer]
A common theme, you know, for the success that I've had is just to go for it.

We went for it, and it worked, and it repeats, and, you know, it's advanced. It was a struggle for even me at first. Like, okay, but how is this actually working? And, you know, we even, we did dynamic scans to make sure it wasn't changes in blood flow.

And, you know, it's, you know, one of the, one of the mantras of scientific research is don't fool yourself. So, you know, we spent, we spent a considerable amount of time making sure we weren't fooling ourselves. You know, we went, we went and, and presented it at SNMMI in, I think, 2016.

And it was, it was a mixed bag. There were people that were like, wow, this is really interesting. There were people that were like, no way, you know.

[Colin Miller]
And in front of SNMMI, that's, that's quite the audience to do it in front of. Yeah. And get the challenge.

Wow. 

[Ben Larimer]
It was unique enough. I was in the Young Investigator Award, you know, in the five finalists, but it was, it was probably too unique.

I didn't win, but that's all right. It was, it was a fun, it was a fun one. 

[Colin Miller]
Yeah.

So do you have any other groups that have actually developed a target on a non-receptor in the radiopharmaceutical world? Is this still unique in its aspect of not truly targeting a cell? 

[Ben Larimer]
There's a, there's an incredible scientist at the Carmanos at Wayne State, Nerissa Viola, and she's done interferon gamma. You know that I, the PARP inhibitor, PARP is a, it's an enzyme that fixes breaks in DNA. And, and it, so it's not a receptor, but yeah, I think it's, we probably, it's impossible to know the entire literature.

I'm sure there's somebody out there that's like, you guys were at first. And we've certainly, there certainly weren't a lot of examples back when we were doing it. None that I could point to, to reassure people.

So maybe that's on me for not keeping up with the literature enough. So yeah, I think some people, I think more people are looking at, at some secreted things in the tumor for sure. Interesting.

[Colin Miller]
Yeah. It would make sense. And in some respects, that's why I asked the question.

You have been a pathfinder in what we're doing and the way we're using these as imaging and biomarkers. And its credibility to you and the team to pull that off. And so, then the next step, if I understand it, is that you formed a company, CytoSite. And how did that come about? And what, as part of that, where's that going? 

[Ben Larimer]
So, we were really fortunate to have some great clinical collaborators. And one of them was a melanoma oncologist by the name of Keith Flaherty. We went to him and he's, wow, he thought it was really cool right off the bat.

So, he'd been advising us, and we said, okay, we've done a bunch of mouse work. He said, okay, what's the next mouse experiment we should do? He said, don't do any more mouse experiments. You need to put this into people.

Yeah, you could do mouse experiments forever. You're never going to know if it's going to work until you put it into people. So, Keith had a lot of experience with advising companies and he's just a, he's a giant in the field of melanoma.

And so, he said, you need to find, you guys are scientists. You need to find some business expertise. Umar had been working with a scientist turned a longtime entrepreneur named Jim Jensen.

He had a different company that we had been doing contract work for. And for a myriad of reasons, he was moving on from that. So, we sat down with him, and we said, hey, we've, we've got this technology. What do you think? And he dug into it for a while. And finally, he came back and said, yeah, I think we've got something here. And he really helped us to understand the business side of things.

And he had had a lot of success previously. And he set up lots of pitch meetings. And eventually we were able to raise a series A and, and CytoSite Bio, the company was, I guess it was born before we raised the series A, but it really blossomed with that series A. 

[Colin Miller]
And now you've ended up in the pole position as CEO. So, you've done the transition from scientist to entrepreneur and business leader. So how do you balance the demands of scientific innovation, business and financial realities of a biotech company? 

[Ben Larimer]
The way I try to think about innovation versus the financial realities is generating value.

I think there's innovation for the sake of innovation and that's important, but that's mostly an academic exercise. And sometimes you have to stack lots of innovations on top of each other for even decades. When you're innovating inside of a company, you really need to ask, okay, how do I generate value to our shareholders, but also value to our partners or, or our clients in the terms of people that we are selling the ability to do grants and imaging to.

You really have to hone in on where can the innovation drive value. And if you're providing value, the finances, at least in the time since I've been running CytoSite, the finances follow. That's a great insight.

[Colin Miller]
And certainly so for any other entrepreneurs out there, appreciate that. And I guess kudos to you because you've just signed the first major partnership deal for CytoSite Bio. Do you just want to briefly explain that? 

[Ben Larimer]
Yeah, we are extremely excited. So, we signed an option to a, to a license agreement with Lantheus, incredible company. You can go look at all the success that they've had developing and commercializing diagnostic agents specifically PET agents. So the science around Granzyme B is really strong.

And I think the data speak for themselves that this is going to have clinical value. And so the question that I, the question that I asked as CEO was how do we get this to people in the fastest and most productive way? And in talking with Lantheus, I think that they represent a potentially very strong partner that can maximize the value of the Granzyme B PET imaging agent. So yeah, so that we just signed that about a month and a half ago and looking forward to working.

[Colin Miller]
Congratulations on, on signing that deal. What advice would you give to other scientists who are entrepreneurs looking at commercializing their discoveries? Both of us, I think mentor folks in that environment. Yeah.

What advice do you give? 

[Ben Larimer]
Find a team, understand. I think we as scientists understand domain expertise in the realm of science, where if you're a PET imaging expert, you're not going to try it and go do neurosurgery, right? It's the same in business. Business is, it's, is, is as complex as any scientific field.

Take a smaller piece of a bigger pie, right? Find a team. The better the team, the better the enterprise. So that would be, don't try to do it.

You're on your own. Don't try to recognize the expertise that's required for business to succeed. 

[Colin Miller]
Yeah.

I'm, I'm with you on that. You always find, yeah, always find people that are better than you around. Sometimes the approach I try and look for, and yeah, Bracken's built a similar structure and you're always looking for folks that can help you in that.

Moving the conversation along a little bit. What do you see as the next frontier in, in biological imaging and cancer diagnostics? You know, you built Cytosite off the back of this. I wonder what you're looking at is seeing if you can look into a crystal ball, what's in the future.

[Ben Larimer]
Yeah. So I think, I think as a field, we've really honed in on characteristics of what makes a good diagnostic agent, one that's injected intravenously for cancer, because what we really, and this builds all the way back to when we started doing genetic sequencing and thinking about each person's cancer as a unique disease, right? This personalized medicine approach to treat the problem with metastatic disease is that you can't biopsy every site. And what we're learning even more recently is that even within your tumor, you can have different kinds of populations of cancer cells.

So that if you take a sample from one part, it may look like this, but another part of your cancer may be completely different. So, one of the values, diagnostics, PET imaging is that we can inject the G anzyme B tracer, and we can see what's going on, not only in your entire tumor, but in all of the tumors in your body. And it can help us to understand, okay, most of the cancer looks like this, but there's one spot that, that looks different, right? And that can help to guide.

We have a, we're very fortunate that we have a lot of different treatment options that are from decently to very effective. And, but we have this paradigm of choice where, you know, we need to, you can only give so many treatments, and you want to find the best treatment for each person. So, I think big picture wise, we're going to continue to be able to develop diagnostics that give us a better picture of what each person's cancer looks like so that they can get the right treatment.

One of the limitations of our field, PET in particular is the cost of scanning. These scanners are complex to build and, and you have to recover the cost. But I think between the advances in just the scanner technology, plus what we're learning about AI and machine learning, I think the wealth of imaging agents that will coming down the pipeline in the next decade, plus the cost will drive the necessity to find a way to reduce the cost of scanning.

Right? And so we can get more access to these amazing PET diagnostics or more patients so that we're not getting shut out by the cost. 

[Colin Miller]
Now that makes sense. And it's amazing how technology does change and grow.

I, because I know some of the imaging that's that you've done, I think the ability of this, of Granzyme B imaging with the CytoSite products, that spatial orientation that it provides way beyond possibly even FDG now has been fascinating to see the heterogeneity that can be observed due to the really key localization of Granzyme B release. 

[Ben Larimer]
Yes. 

[Colin Miller]
To me, phenomenal.

And I'm not certain that has really yet been expanded in, in the imaging world, whether it's Granzyme B imaging or anything else.

[Ben Larimer]
One of the things that, that has been useful for us, and I think other people are finding useful is, is that FDG is certainly very valuable, but it has limitations and Granzyme B can differentiate. One of the limitations of FDG is that both cancer cells and very active immune cells both eat a lot of sugar.

So you can't tell, oh my gosh, is this high amount of PET signal I'm seeing from FDG? Is this that the cancer's growing or becoming more active? Or is it that the immune system is there? Granzyme B, cancer cells aren't secreting Granzyme B. So if you see high FDG, but high Granzyme, hey, there's immune cells there and they're releasing Granzyme B. And if immune cells release Granzyme B, cancer dies. And like you said, we've seen these clinical images where even in, even within a single tumor, you have areas of high Granzyme B and areas of low Granzyme B. And the part that has high Granzyme B, but we follow it up, part is dead. And when the part that is low Granzyme B, when we follow it up, it's, it's progressing.

So that helps you from a patient perspective, but even from a drug development perspective, you can see if a patient, if your drug works in four of the five tumors within a patient, that's still going to be progression on the, by, by the standard measure that we use, which is called resist, which is basically have any of your cancers grown bigger, especially early on in drug development. You may, you want to see, does the mechanism of action that I'm investigating, is it working right? And seeing that in four of those five lesions, you get lots of Granzyme B release and one there's not, that gives you information that you wouldn't otherwise have using just, just FDG and CT. 

[Colin Miller]
And that's the key to really where you were at the beginning of creating value. And that's what you said about being an entrepreneur. It has to create that value prop. And I like the way you've brought it all the way around a full circle again.

I appreciate that. So with this, with your career, you've obviously had some highlights and some, probably some tough times as well. What would you say would be your toughest time perhaps? And your…And your highest. Yeah. Yeah.

[Ben Larimer]
I'll start with the, I'll start with the low light. So drug discovery is, is 99. It's 99% failure before you ever have a success.

And so, you know, right around the fourth year of my PhD, I was learning face display. I tried to develop things, and I had nothing, no papers. And I was just like, what did I do? So, I actually went and audited a law school class.

To me, they were talking about invalidating. How do you invalidate someone's patent or something along those lines? And I thought, Oh my God, you know what? This sounds terrible as well. What am I going to do? And luckily stuck with it and was able to develop, complete my PhD.

But I specifically remember sitting in this law class being like, have I made a terrible mistake doing this whole PhD thing? I'm never going to graduate. And I think all of us who have done PhDs have probably been at that point. It is, it's not for the faint of heart, but that that's probably the low light of my career.

In terms of the highlight, I think, yeah, I've been lucky to have this, this Granzyme B agent go into people. So I, I remember that day. The first patient was going to be scanned and maybe this was like a low light into a highlight.

I had a moment of panic. This is a molecule that I designed and made. Obviously I didn't physically make this exact thing that was going into a patient, but when we'd done safety and all of that, but there's still like this 0.01% of, what if things go terribly wrong? When we check this into this patient after the patient had been dosed and it was the first patient ever.

And we were all excited and we looked, and we looked good. So, I think that, that was, that was, that's probably been the highlight of my career so far is to be fortunate enough to have something that I remember working on bench going to go into people and be safe so far. And it also shows some promise.

[Colin Miller]
Because I was involved with that and appreciate hearing that because that was quite the day. I, yeah. I also recall that because there are very few days in your career for any of us that were involved in getting a first into human, literally the first day, the first time you put a drug in.

And yeah, cause I was collaborating with you. I, I, I, I remember the probably as much tension from a different angle. I didn't care in one respect what it looked like.

It was all the operational character. 

[Ben Larimer]
Yeah. Yeah.

No, we, we worked, we worked, you know, side by side on that for a long time, getting it through and getting through all the speed bumps. So yes, that was a fun day for every, for everybody. Yeah. At CytoSite, and all our partners like Bracken. It was, it was cool. It really was. It's been a great journey. 

[Colin Miller]
It has. I also still think that first patient was almost unbelievable in the amount of information that we learned just from that first patient.

It was, there was so much signal in the right places that we not have asked for that combination to really, okay, let's keep going. 

[Ben Larimer]
Yeah. Yeah.It was, yeah, it was very cool to see. 

[Colin Miller]
Oh, again, congratulations and kudos. That was a lot of work and I was really riding on the coattails there rather than so to you and the team that pulled that one off.

That was appreciated. So now having done this sort of development, if you were given an hour, a hundred million dollars to spend in industry or society, where would you invest it? And why? 

[Ben Larimer]
CytoSite. So, we're developing a radiotherapy.

So of course, I would say I'd invested in CytoSite at least, but I don't think that's, I don't think that's the most interesting answer. So, I, I think I'm probably biased, but I think nuclear is, I think it has a lot of potential to impact talking about industry or society, bigger picture. We're, and tying AI into all of this, we're going to need a lot of electrons, a lot of electrons to, to handle all of the AI that we're doing.

And I think we all want the cleanest way to produce electrons possible. Getting away from fossil fuels is, is important. And obviously nuclear is a very clean technology.

It has risks as all of us are aware, but I think that, I think that nuclear, these newer generation nuclear reactors are, are much different than the ones that are famous for their problems. And simultaneously, these nuclear reactors, my alma mater, Mizzou just, just announced that they're going to be building a new research reactor, but these reactors can produce isotopes that can be very helpful for patient treatment as well. It's a little bit near and dear to my heart, but the ability to produce clean energy, which has a good impact on the environment, plus give us enough electrons to use, to use AI to, to advance medicine.

And then, hey, as a by-product, we'll take those, we'll take those spent nuclear reactions and, and turn them into medicine. That, that's my big picture, how I would, how I, obviously a hundred million is a drop in the bucket for some of these nuclear reactors, but I'd at least, I'd at least chip in, because I think for the most impact that, that would be my answer.

[Colin Miller]
That's a clever twist on, on, on the challenges. So maybe we should increase it to a hundred billion and build your own.

[Ben Larimer]
Yeah, I think, I think the price tag on the Mizzou reactor was like 10 billion and that's a research reactor, obviously, so different, but, and I'm not, I'm also not a nuclear engineer, but yeah, I think, I don't know that, that kind of touches, that touches a lot of, a lot of boxes and as that dual, helpful for society plus helps generate returns.

[Colin Miller]
Yeah. It's that duality that I think has a unique perspective. Fantastic.

And so really our final question that we like to ask people is, you speak with yourself at a younger age, 25, 20, somewhere in your early career. What advice would you offer yourself?

[Ben Larimer]
I wouldn't want to change the way things have gone for me. I like how everything's turned out. I think some of the struggles have led to some of the successes.

So I wouldn't jinx myself by going back and giving myself advice. Now, obviously I wear two hats. One, I'm the CEO of CytoSite, but I also am a professor at UAB. And so, I actually give advice to 25 year olds like daily. So, you know, what I try to tell these PhD students who I was telling the low light of my career being that struggle, what I try to tell people who are smart, scientifically inclined, what I try to tell them is there's a lot of ways that you can be a scientist or make an impact in science, impact in medicine that are outside of the traditional academic pathway. 

And I think that one, I've been fortunate enough to see these, there's just a lot of professors that have worked their butts off to win very competitive race, getting from getting into a PhD program, getting into a postdoc, and then getting each level of that is even harder getting a professor position, but that's all they've seen.

And, and you've seen, obviously you've seen a whole breadth of things wider than I have, but I've been able, I've been fortunate to see different parts of this as well. I wish that we, as, as universities and professors would do a better job of exposing these students at a time where they're learning, but also trying to set up the rest of their career. We should be doing a better job of exposing them to all the different ways that they can, they can make an impact.

They can generate values like my thing, but it, because we're kidding ourselves. No, most of these students will not become professors. It's just a, it's a numbers game, but that's all we, that's all we train them on.

So, I think, you know, when I try to tell students who are interested in sciences is look at, look outside, look at a whole breadth of things. And maybe being a professor is your career path, but at least you've looked at a whole different range of things because I don't think, I don't think we do a good enough job. And I think that if I'm being critical of me or us with our academic hats on, we'll often hear, Oh, if you go into industry, it's going to be so boring.

Man, there are so many awesome, smart scientists that it's just not true. There's a lot of cool, innovative work being done. That's what I, that's how I would tell people is go out, go out and look because it's different, everything from drug discovery to even figuring out how to get this drug safely into people for the first time, like we did together, or how do I design a trial so that I can get this drug to market?

There is no formula for this and you're still putting, you're still doing science. It's just a different, it's just a different hypothesis.

[Colin Miller]
Thank you, Ben. And because you're a professor as well as an entrepreneur, you've, you're one of the very few people that have their foot in both camps and maintain it in both camps and can see both sides to it. And so that is a truly fascinating insight and approach.

And I wish you well with your, with your current PhD students and also with the development of cytoside and the way it's growing, I think kudos to the way you've been able to navigate that and bring the value propositions and actually change incrementally the potential for the treatment and therapy for patients and the lifespan, so really appreciate it. So thank you for joining me today.

[Ben Larimer]
Yeah, I really appreciate the chance to talk with you. I think we've worked together for a long time. It's, it's, it's been a fun, fun conversation.

[Colin Miller]
Fractals is brought to you by Bracken, the professional services firm for life science and digital health organizations. Subscribe to Fractals via your preferred podcast platform. Visit us at thebrackengroup.com or reach out directly on LinkedIn. We'll be delighted to speak with you.

I'm Colin Miller, wishing you sound business and good health. Thanks for listening.