Good Unicorn Orca Bio is solving cancer.
And not just any cancer, but some of the most aggressive forms of terminal cancer: acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myelodysplastic syndrome (MDS).
How?
For over 50 years, the stem cell transplant has been terminally ill patients’ best hope for a cure.
In these transplants, patients receive over 100 billion cells from a healthy donor, but less than 1 percent will create therapeutic benefit. Of those who survive this treatment, 40 percent will die in the first three years due to relapse, lifelong debilitating conditions like chronic Graft versus Host Disease (or GvHD), organ failure, or infection.
What causes this 40 percent relapse and mortality rate? Those extra 99.5 billion cells that continue to float around in a patient’s body are limiting the therapeutically active cells from achieving their optimal effect.
What Orca Bio has invented is a way to isolate the less than 1 percent of the 100 billion cells that patients actually need in a stem cell transplant, so the rest of the cells never enter a patient’s body.
The precision-cell selection biotechnology approach that Orca Bio has developed not only has the potential to solve cancer and relapses, but also hundreds of diseases in the future. Let’s dive into the deep end with Ivan Dimov, PhD engineer, CEO, and cofounder of Orca Bio.
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Diana Tsai: So thank you for doing all you’re doing, you’re doing very important work. And I need to get you back to it as soon as possible since you’re actually solving cancer. So we’ll try to make this as succinct as possible. Can you share what you’re most excited about with Orca Bio’s major breakthroughs?
Ivan Dimov: We’re on the path toward pursuing FDA approval, and anecdotally, the hospitals that have had the chance to treat 160+ patients with our products in our clinical trials have seen this miraculous effect in their patients. So much so that they feel that they have this ethical problem now, because we can treat cancer so much more effectively than what’s currently available. That’s driven huge enrollment into our trials, because it’s not an FDA approved drug yet. So we’re working with the FDA to advance the trials to make it available in the near future.
Ultimately, on top of this, what gets me very excited is that we started with this initial vision of being able to replace and reprogram people’s blood and immune systems. And that’s a very powerful thing to be able to do. What this next-generation medicine is doing is showing us that it’s possible to do this safely and effectively. The implications are profound for dozens of other disease areas. I don’t know if you’ve seen this, but whenever you start a new project, everyone’s very excited initially, and over time realizes how hard it is. And it becomes less and less exciting. And then most of the time projects just kind of die on the vine and people move on to other things.
Orca is one of the very few times in my life where it’s been the opposite, where the more you do, the more excited you get, and the more you want to achieve, with more opportunities opening up as you go.
Tsai: Incredible, I have literally 500 million questions for you. Let’s start with, when you imagine Orca Bio at its very fullest expression, what is the greatest impact you hope you can create for our people and planet? What will this company become?
Dimov: Great question. If you look at how therapies have evolved over the generations, at the beginning we had small molecules, your aspirins, your Tylenols, it’s all the classical medicine. They’re amazing but have limitations. A really big revolution happened in the 90s with the ability to build therapies out of proteins. Proteins are the building blocks of life. And so that gives you a lot more knobs that you can turn and twist to be able to control what happens in the body and therefore fix their diseases. But the ultimate expression is one level above that, and that is the unit of life itself – the cell. And what we do is we build cell therapies where the active ingredients are essentially these living cells. And with living cells, you can do what is basically science fiction today, right?
I mean, just to give you a little crazy idea, which is actually being done already today: imagine if I could build a medicine where I could fight your cancer by infusing the medicine into you, and then have the medicine detect the cancer, multiply, mount a powerful attack, obliterate the cancer, then whittle itself back down to some minimal expression to stay hibernating in your body and re-grow if the cancer ever comes back again. It sounds almost impossible. You could never do that with a pill or with a protein. But you can do that with a cell and that’s essentially what cell therapies are doing today. They’re able to address completely intractable diseases where technically these people are going to die, and they have no other option, everything else has failed, and now, there is this living medicine. You can bring these patients from the verge of death and really give them the possibility of a cure.
Let’s think about a different potential application where you can maybe regenerate a piece of the heart after you’ve had a heart attack and your muscle was destroyed. Using a cell therapy you can also potentially fix a part of your nervous system and your brain after it’s been degenerated by a degenerative cognitive disease that we have absolutely no medicines for today. So I think this idea of cell therapies that’s emerging is going to be revolutionary. We’ve already seen the initial glimpses of it, and it’s created a huge stir in the broader healthcare industry.
So what we built is on top of this cell therapy revolution. This is at the heart of Orca Bio. What I described was cell therapy 1.0. To get to cell therapy 2.0, you need to improve the precision of the cells that are put into the patient. And that’s where our breakthrough exists as a company, in the precision of the selection of cells, because without that precision, you get a 40% relapse rate after bone marrow transplants in cancer patients.
And it has the potential to treat so much more than cancer. Because if we’re able to bring in the exact right healthy cells, we can essentially fix a faulty immune system and reprogram it. We can solve genetic disorders of the blood, things like sickle cell disease and beta thalassemia. We can solve diseases of the immune system. And bigger diseases like type I diabetes or inflammatory bowel disease or multiple sclerosis. Huge diseases that if you look in the last few decades, there haven’t been many approaches to significantly affecting the course of these diseases, let alone curing them.
But now I think we’re on the verge of potentially doing things like that by reprogramming the whole blood immune system for you. And that’s just the beginning. Because with high-precision cell therapies, we can now expand into other genres of cell therapies where we could potentially give you cells that can regenerate in your body, build portions that were destroyed over time, with aging. So it’s a very exciting time to be in this, you know, day and age.
I was just really shocked at how quickly our first application is bearing fruit and very, very humbled to see how people who were basically hopeless all of a sudden, three, four years later have no disease whatsoever. As an example, one of our patients, he had a terminal blood cancer. His wife was just recently pregnant and it was really a hopeless situation. We gave him the medicine, everything went really, really well.
Four or five years later we met him, and, and we asked him, “You were on your death bed and now you seem recovered! What other meds are you on now?” And he said, “You know, the only medication I’m taking is vitamin D. And that’s because my wife makes me take it. What’s really cool though is that before I went through all this, I had a bunch of white hairs. But now that I’ve gone through your treatment, I’ve recovered my hair, and I don’t have any white hair anymore.” It’s a side effect! And so it was just so incredible to hear that kind of story, even the little things like the hair.
Tsai: I mean, the little thing that you just just described, hair regrowth is actually another billion dollar company. Maybe a little more superficial of a Unicorn. But definitely another one.
Dimov: Plan D if all else fails.
Tsai: Haha. So how did you figure out this entire precision cell-therapy solution?
Dimov: So throughout my career I’ve been fortunate to start a few other companies as well. What I noticed is that you need to find where the nails are and what needs to be hammered before you can design the best hammer. As that classic wisdom says, don’t just build a hammer and then go looking for nails because at that point everything looks like a nail. So that was a lesson that I learned the hard way with a couple of failures in the past. With Orca, I was trying to understand the major issues that were there in this field. I was fortunate enough to work with a gentleman at Stanford, Irv Weissman, who is a living legend and scientist who really pioneered the whole cell therapy field. One of the companies he was involved in during the 1990s was seeking to solve terminal breast cancer. They did it with a very early form of cell therapy. And on the back of some early promising data they were acquired for a pretty significant amount back in those days by a large pharmaceutical company.
However, a couple years later, the whole venture got shut down by that large pharma acquirer. And it was even more sad when, 10 years later, we went back to look at what happened to those 40 initial patients. And we could see the cure rates, and this is like 12 years on, we could see that the cure rates for these incurable patients were 2 to 3x what you’d have expected normally. And the treatment was shut down! For me, that was an ethical issue. Here’s a situation where for about a decade, we’ve known what to do to really save a lot of people’s lives, but we weren’t doing it and were letting them die. If you just did a back of the envelope calculation of how many lives you could have saved with breast cancer, it was this huge ethical problem.
Now, one of the big reasons they shut it down was this problem with manufacturing and high precision – you really needed high precision to be able to manufacture and scale the therapy. And the problem was that the existing tools on the manufacturing side did not allow you to do so. So you could create a treatment for some patients, but to build a scalable business out of it, it didn’t make sense. It was just untenable. That was the inspiration for us: if we can fix the manufacturing problem, which is a much lower risk problem than understanding biology and creating brand new medicine, then we can save people’s lives.
Tsai: Got it. And when you talk about manufacturing, just to clarify, because I actually have no science background, I’m very bad at science, which is really good because from an audience perspective, I think if I can understand the science then anyone will understand what’s happening here. So when you say manufacturing, you mean the same thing as this precision cell selection process that sorts every single cell from 100 billion?
Dimov: Yes, exactly.
Tsai: Ok so, can we talk about how your core innovation of sorting the 1 cell from 100 billion cells makes this affordable?
Dimov: Sure, I think I can explain it in a relatively straightforward manner. When you need a high level of precision, you have to go down to the single cell level, meaning you have to measure every single cell and make a decision if you want it or not. So this is done with a cell sorter, we call it a FACS machine. Not the fax machine that sends you documents. This FACS machine lines your cells up and flies them through the air very, very quickly. As they fly through, they go in front of a laser, and the laser analyzes the cell and figures out what it is, and then a deflector plate knocks the right cells out of the stream for use in a patient.
The big challenge is that if you want to do this more efficiently and faster, which you need to with 100 billion cells, you have to make the cells move faster and faster. The problem is the cells are fragile, and at supersonic speeds, you’re creating so much stress on the cells that they break. In other words, the speed by which you can process these cells is limited by their fragility.
So what we figured out was, this is silly, this is not the right way to approach this. You really want to push the envelope, what you have to do is stabilize the most fragile thing you have, which is a cell. So instead of flying it at supersonic speeds, keep it still and then move everything else past the cells. Move the lasers, move the deflectors, move everything else past because those are hardy things and they’re not going to get damaged if you fly them around very quickly, but cells will. So keep the cells still and move everything else past. And so that was the genesis of it. It’s a very simple idea.
And now the question is, how do you then get the specific <1% of cells you want out of the array of 100 billion quickly once you identify it? That’s where the real true innovation was. And this is something we just stumbled on based on some really cool physics. It turns out that the same laser you’re using to find the cell can also essentially inject that light energy into the section of the cell array where the specific cell you want is and cause the cell to pop out of the array, after which it’s mechanically sorted into a separate container. So all of a sudden, you’re both identifying and extracting those cells with the same lasers. And that is key because lasers are extremely fast. Lasers can sort millions of cells per second. And if you compare that to the old FACS machine method, that was tens of thousands of cells per second. So you’re now 100x, 1000x faster by changing the architecture and leveraging technologies that were developed for the semiconductor and consumer electronics industries for completely different uses. But now you’re putting it to use on cells, which enables a whole new genre of medicine. And it’s really, it’s elegant, because you’re standing on the shoulders of people who came before you. We just rejiggered it in a slightly different way and now have a whole new set of applications in a completely different industry.
This brings me to what really matters though, another patient story. We had a terminal blood cancer patient, she had all these wounds in her digestive system, she wasn’t able to eat, she was relatively young, in her 30s, and had her whole life ahead of her. And she was really essentially in hospice care. She got our medicine, and relatively soon her wounds started healing, her infections and other issues started disappearing. A couple of weeks or so later, she was discharged from the hospital. And then we heard that about a month after her discharge she was doing six mile hikes on the weekends. It’s just incredible to see that and know that all the failures are now worth it. It’s been a long journey.
The FDA has also been a great partner with us. I think that they know when you have something that’s novel and exciting, they recognize it. They’re very rigorous and scientific. And so if you have a very rigorous scientific approach, they’re actually very collaborative, bring a lot of knowledge, and can give you some good feedback and advice. And so it’s all worked in the right direction. Right now, we’re really excited to be in the final stages of the development, to have line of sight to a day in the not too distant future where we can make this treatment available to everyone that needs it.
Still, it’s heartbreaking when you hear about people out there that could have been potentially helped, but we just weren’t ready enough to help everyone.
Tsai: How do you balance that from a psychological and emotional perspective? Because I already heard this earlier in your story when you’re explaining the issue with the breast cancer patients. I can’t imagine the sense of urgency you constantly feel because people are actually dying when you know you’ve created something that can save them. So, how do you stay sane?
Dimov: It’s a lot of emotions. It’s a lot. I think, ultimately, what calms me down is this idea that if I overdo it on a specific case, and I lose track of the big picture, at the end you might have saved this one person, but you lost the possibility of saving hundreds of thousands behind them. When I think about it from that perspective, it becomes a little more manageable. It is important to have this urgency, it’s important to go fast. But it’s also important not to screw it up. Because if you go too fast, you screw it up, and when you screw it up, you’ve screwed it up for many more patients than the few that you could have saved by pushing it too hard right now, right? So you have to go slow on certain things because that’s going to enable you to get to the real goal more quickly, which is getting that FDA approval and getting it out to hundreds of thousands of people. So that’s how I see two forces kind of balancing themselves out.
Tsai: That’s an incredible response. Thank you for that. I also have to say, you have a patient who is now hiking six miles, another patient who regrew his hair…I don’t know if this is the intention, but you’re not just solving their disease, you’re also turning them into super humans. Everything you’ve done is incredible. Can we flip now to talking about some of the failures along the way? What’s it taken to get to this point?
Dimov: Yeah, it’s a great question. Part of these failures have been mine, part learned from other people. One of the unfair things is that if I just dwell on what I failed at, then that’s going to give you a biased perspective, because a lot of big failures had to happen in the past to make this possible. Failure is a key part of the process because failure is incredibly valuable. It’s the key to tell you what not to do later. So from that perspective, you know, if you think about failures, maybe we’ve gone through 50 to 100 different prototypes on the technology of the machine. Overall, it’s hard to put a number on. There are so many different variables here. But in the end, you’re always progressing. You’re always doing better than before. And when you know you’re doing better than before, even if you haven’t solved that, you just keep at it, and sooner or later, you’re going to solve it.
Tsai: That’s a powerful perspective on failure and a humble one. I want to ask you about affordability. How will you make this treatment affordable, accessible?
Dimov: These kinds of treatments are usually reimbursed, so you have the sort of medical access system to help with affordability. But there’s a bigger picture. Because we’re dramatically reducing the 40% relapse and chronic disease rate, we’re potentially saving the healthcare system money long term.
I think the biggest challenge to access here is the ability to generate enough of these products to be able to give it to everyone that needs it, which is more of a scalable manufacturing challenge, less of an affordability issue.
Tsai: Okay, so I’ve been now coming back to your personal journey, you had mentioned a little bit about failures in the past, etc. What I mean, what brought you to this moment? And how was this personal to you?
Dimov: Great questions. I’ve always been fascinated by innovation and discovering new things, developing new solutions, new technologies. And that’s what drove me initially to research and academia, and I’ve been quite involved in academia. What happened is that I was a bit disappointed, because most of the time in the academic realm, you come up with some really creative solutions, you publish them, you create a lot of buzz around them. But then you move on to the next thing, you don’t actually take them further on. To some extent, it’s stifled. And so I very quickly realized that I also need to do the rest of the job. I can’t just come up with a cool idea and move on. I have to work really hard to bring this to people out there. And I think startups are just an amazing tool for precisely that, creating new solutions.
At the end of day, you ask yourself, how do you want to help society? And one of the most meaningful ways to help is when you can really literally save a life, right? I mean, the most precious thing here is a human life. Certainly more precious than making vacations easier or getting a pizza faster to their home. I mean, those are all good things. But saving a life, that’s a different scale of impact. So I realized that biology is where I could do this. And furthermore, I realized that in biology, there’s so many problems to solve, there’s so much stuff to figure out that it’s really, really exciting. Probably more than most other spaces. And the more I got involved, the more I got excited about the new possibilities of these new modalities of therapies because if you look at the biggest problems that we’ve had, in general, as a society, cancer is definitely up there. I think the war on cancer was declared in the era of Richard Nixon. We’re still fighting it. And that was ages ago. So it’s such a hard problem. And you need new technologies, you need new tools, you need new science to really go after this.
Tsai: I love your analogies here. I know you’re very passionate about patient stories. Before we end, are there any other patient stories you’d like to share?
Dimov: Thank you for asking. Honestly, I’d love to meet all 160 that have gone through the trial. Sometimes I mentally imagine if I could see all of them in one hall or theater, they’re all sitting there, what would it feel like to see all these people you’ve touched in front of you? That must be an incredible feeling. But unfortunately, we haven’t had an opportunity to do something like this yet. We’ve only had a chance to interact with a very, very select number of them who have been willing to connect with us. And so I haven’t heard all their stories. But I’ve heard some, and here’s another one.
What excited me also about this patient is that she also spent most of her life working to develop medicines at several really large and successful pharma companies. And it was great for us to actually sit down and talk about the details of the science with this patient, and tell them all the things that we tried, and we didn’t try.
We were also very humbled by the fact that she was also one of those first patients to get onto this trial. When you’re one of the first patients on a trial, you don’t know if it’s going to work. It’s a huge, huge risk that this person is taking. If I’m in their shoes, it’s extremely scary. And so I am very honored when somebody puts their life in our hands in order to further this cause.
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