Episode Transcript
[00:00:00] Speaker A: Hello, Boro. Thanks again for taking the time with us today, starting from the very beginning, what brought you into medicine?
[00:00:06] Speaker B: Well, thanks for having me here today, and I really appreciate your interest.
I've been a scientist for over 30 years. I graduated as a virologist from Australia, and then I had the great opportunity to come to the National Institutes of Health, travel across the Pacific and into the Washington, DC area. And the cool project that I had was to turning viruses that normally cause disease into vectors to help war disease. So that really interested me, you know, converting swords into plowshares idea, if you like.
But yeah, I've been in this space now and really working on a specific type of vector derived from HIV. So what makes HIV such an insidious and stealth like virus and difficult to cure? When you turn it into a vector, it becomes a very efficient way of delivering genes into cells and then creating cells that can then have tremendous therapeutic outcome. And we've seen that with CAR T cell therapy, whereby you can genetically engineer t cells in order for them to go and find and kill cancer cells and transformative for patients and in many cases cured of their disease. My journey has been first at the NIH, then in academia. I was a faculty at Johns Hopkins University.
And then I kind of crossed over to the dark side, started some company, and we were able to actually the very first lentiviral vector placed into humans and to establish safety. That was my team. We did that in collaboration with my colleagues at the University of Pennsylvania. And then later I started a company called Lentigen, lentiviral vectors and genes. And we were the group on my team were able to construct a vector that eventually became Kimriya, the first FDA approved product, gene therapy product for the treatment of leukemia. So been in the space, made some contributions, and then very interested in making sure that these medicines get out to the people who need them. That's the genesis behind Keirin Crosse.
[00:02:23] Speaker A: Thank you for sharing. I find myself really interested in hearing how you've been able to do this in the past and that you keep doing it. What about building teams and diving into this space interests and fascinates you so much that you keep doing it in different iterations?
[00:02:39] Speaker B: Yeah, building first a team in an academic research center, relatively small team, then starting a couple of companies, building teams of 50 and more people, and now a nonprofit team leading that organization.
And really the team is the key, I think, for success and the culture of around the team that you create is key to success.
And I'll be very fortunate and blessed to have many fantastic people working with me and sharing a common vision, right, that we want these therapies to work. We want them to be safe and efficacious, but we also want them to get to patients who desperately need them. And under the iteration of Caring Cross, where I am presently leading that organization, we're really trying to focus on affordability and access. We know that these therapies work. They can be curative. And I think we're at the very letter a of a whole new pillar of medicine, if you like, and simply engineering to make them more and more effective. But the key is affordability. Right now, very few patients, relatively speaking, getting access to these therapies. And part of the reason for that is the very, very high cost. When you have a high cost, insurance companies are more reluctant to approve them.
Also, in low middle income countries, it's very difficult to pay such a high price. These are just the price of the product. Hundreds of thousands of dollars, 400,000, 500,000, 2 million, 3 million. It's not really affordable and sustainable anywhere, let alone in low and middle income countries, which we're particularly focused upon. So we're focused on a couple of different aspects. One, lowering the cost of manufacturing, really focused on inexpensive and affordable work processes to manufacture these CAR t and other cellar gene therapy products. Then the cost of the materials that makes the final product, like, for example, the vector, decreasing that cost, and then a way of distribution. Right now, many of these products, because they're the cells, are taken from patients and then returned back to the patients. They undergo this very cumbersome, centralized manufacturing. They're sent to a facility, one located in a continent, manufactured there and sent back. That is very expensive to set up and to maintain. And we believe is in point of care manufacturing, where we can enable hospitals to manufacture these products cost effectively, locally, inexpensively, so that they can be fully reimbursable and made affordable and available geographically in diverse areas. So the greatest number of patients can get access to these therapies.
[00:05:15] Speaker A: What do you feel is the driving difference between you and other?
[00:05:19] Speaker B: Yeah, it's a couple of things. It's focused on decreasing the cost of the process and decrease in the time for manufacturing cost of the components of it. That's one aspect. Another aspect is the point of care manufacturing, working with hospitals, because they will produce it very cost effectively. But the third also is technology transfer.
For example, we are working with an organization, another nonprofit called, it's the foundation. It's called Fiacruz, which is located in Brazil, that is funded by the Ministry of Health in Brazil.
And we're technology transferring all the knowledge needed to make the CAR T cells, to make the vectors that they can produce these products less than one 10th of the cost of the approved products in the US and in Europe. So it's a couple of different ways that we are trying to improve affordability and access around the world.
[00:06:16] Speaker A: How are you able to even identify that this was a gap to go into, like decreasing the cost? And what motivated and drove you to do that?
[00:06:24] Speaker B: Yes. So the motivation was very easy when you're part of the equation of helping to move these therapies along as a field, as so many of my collaborators and colleagues have been, our reason of doing this as scientists, is so that patients can get treated. That's the reason why we're doing this. Yeah, I mean, and then when you see that ultimately the approved products are treating relatively a few number of patients, and the barriers are the high cost and the delivery systems for access, because that's delaying access to centralized manufacturing, for me, it was very important to try to address those issues, even as a scientist. Right. And because we have the knowledge, myself and my team, we've been doing this for a very, very long time, we are in a good position to technology transfer to countries like Brazil. We're in a position to develop low cost vectors. We're in a position to develop low cost manufacturing platforms for CAr T and then transfer those technologies to those that will ultimately make them. Why not? I mean, this is the very first. This is the reason why we're in the field to begin with and we're in a position to do it and we intend to do it.
[00:07:34] Speaker A: Yeah. It really is a shame when science advances so profoundly and the barriers is money, especially because, as you were saying, like, these immunotherapies are so efficacious. It really is a shame when the number one barrier is cost. And so, going back to the partnerships that you were alluding to earlier, so can you just talk a little bit about the vision behind how you continue to expand it and what you're thinking of looking for in the future?
[00:08:01] Speaker B: Yeah, I'm thinking expanding the current model. Like, we are transferring this technology to our partners in Brazil. We intend to do that in other places around the world. We have conversations in other regions of the world to do exactly the same thing and then also initiate clinical trials and develop these products through hospitals directly.
They are actually the innovators of the field. So we want to continue to work with them to innovate, run clinical trials, and take these products to approval and then create, let's say, a manufacturing or product cost equation that really becomes acceptable to public health systems like Medicare and Medicaid, or national health insurance systems, for example, in Europe and other countries. And it's already shown to work.
Colleagues in Spain, and particularly a group from Barcelona, have been able to create a network within Spain, about ten sites where they're working directly with hospitals providing the vector, providing some of the materials. Some of the materials are bought off the shelf, and the cost of the product is about $100,000, right. Which many insurers will pay, gladly pay for these products. It's just when the price becomes, you know, 300 and 5400, 500, a million, that becomes much more difficult from the perspective of insurers to really approve them, you know, very readily. So we're trying to get to a point where insurers see the value that at a certain price point, they will just automatically approve so these patients can be treated, so they have the best chance for dealing with their disease and get the products as soon as possible. That's very important. Sometimes the delays in approval of the therapy results in some patients not receiving the products in time. It's not only true for insurance approval, but it's also true for when you have a long manufacturing cycle that also results in some patients with advanced disease not receiving the product in time. So we're very much about reducing the time, reducing the cost, putting it local, everything that removes barriers for patients to be able to get these products as soon as possible in an affordable way, that national insurance systems in particular will pay for these products.
[00:10:16] Speaker A: And so a couple of questions on that, especially because I want to go back to a point where you had highlighted the hospital communities of being the real innovators within this process. Is it because they're able to decrease the time, because it's in house and decrease that barrier of cost? Like how?
[00:10:31] Speaker B: Because they're relatively free from other concerns to drive innovation. They have an idea and they'll develop it, rather than necessarily having to sort of like, get approval to work on a project, because the market has to be a certain size in order for the company to make the investment to move forward. Right? They're free, they're scientists developing, and it's through that freedom that a lot of innovation is actually created. So the academic environment, we find, is the most fruitful place where new ideas and new therapies are developed because they have that kind of. That freedom.
[00:11:04] Speaker A: Yeah, that's really interesting. Can you, in your experience, talk about a time where using that freedom has allowed you to impact a patient.
[00:11:12] Speaker B: So having that freedom recently at Hopkins and then basically forming that first company and moving forward with the first trial allowed us to show that these vectors were safe. And given that the number of products now that have been approved using lentiviral vectors, I think that has had tremendous impact on many patients. But then, you know, working with our colleagues at the University of Pennsylvania, those first car ts that came out, and we saw transformative benefits for these immediate patients. It's very gratifying to be in the field to make small contributions, however, you know, however small, to be able to make sure that, you know, you're working with the right people so that these innovations can get translated and then get to the. The people that need these therapies. And that's true not only for my Upenn colleagues, I've had a long standing collaboration with colleagues at Case Western, at UC Davis, at Ohio State University, and others. So, I mean, it's all, working with great people at these clinical centers makes all the real difference.
[00:12:17] Speaker A: Yeah, yeah, I can definitely see that. And as you're telling your story, I'm also really curious to hear for you that first clinical trial, like, using that freedom and empowering yourself to go out after that first therapy, that first molecule. Can you talk about the story for you surrounding that? Like, what empowered you to go for it in that first iteration?
[00:12:37] Speaker B: Many people thought I was crazy to take a HIV vector and to put it into humans, but I rationalized that because the vector is so effective, we're going to have to use this type of a vector. Right. And really, it's that rationale of thinking logically.
To get gene therapies to work, you want to use the best possible vector. And then whatever other hills and challenges that you have to meet to get there, you'll do that because, you know, the end result is worth it, because you'll have a vector. And as it turns out, lentiviral vectors are very efficient. There may be other vectors in the future, but the particular properties of lentiviral vectors make them highly efficient in transducing cells. And. And I think having multiple approved products really proves that. So, really, maybe a little bit of craziness in the beginning, but a belief, a deep belief, that this can create a tremendous value for patients in the future. I think that's probably what drove me the most.
[00:13:41] Speaker A: Yeah, I feel like that's. Isn't that a cornerstone behind a lot of innovation? Usually people think, you know, people think you're a little crazy in the beginning, but it ends up working.
[00:13:50] Speaker B: Oh, yeah. No, no. A lot of people, I had people tell me that the FDA will never allow you to take this test.
And I can tell you that I had many meetings, very large meetings with the FDA and very extensive meetings. But in the end, I think they saw the logic that I was proposing and they saw the data, the safety data that we had generated, and they said that this was the correct study to evaluate this, and we were very glad to do everything correctly and then shown the data that this class of vectors were safe. And now they're widely utilized as a result of those first clinical trials that we led.
[00:14:31] Speaker A: Yeah. So then on the heels of that craziness, and I say that. I say that with kindness, but looking now towards the future for the next ten years, I mean, the way science has evolved, even in the past ten years, from, like, branching into car T cells. And then I. I'm just really curious to hear what your insights and what your beliefs are for how this can continue to grow and improve.
[00:14:53] Speaker B: Yeah, absolutely. There have been a series of recent papers that have been using lentiviral vector CAR T cells for the treatment of autoimmune disease, with complete cures occurring. So really amazing kind of data that's out there for leukemia and lymphoma. We've also now seen very good results for multiple myeloma using a lentiviral vector and transducing a stem cell. Right. A hemopoietic stem cell from the bone marrow leads to cures for diseases like sickle cell and beta thalassemia. The problem is the price, right. When it's at two or $3 million, that's untenable. And so part of our role is how do we reduce that cost tenfold, more than ten fold, you know, 20 fold, 30 fold, you know, and so that's what we're doing, actively doing. And I think we have an angle. And part of the solution is, if more efficient technology to produce the vector at a higher level. So the vector cost is not as high. So that's one of the pieces of the puzzle, and we're working actively on that. But I see a tremendous future. We've got currently a clinical trial where we have a car targeted against HIV. So I see a future in using this type of therapy for the treatment of various infectious diseases, particularly chronic infectious diseases, genetic diseases, other genetic diseases other than, for example, sickle cell and thalassemia. Cures have been found for adrenal leukodystrophy and other specific genetic diseases.
So I think there are many serious diseases that will be treated by these kind of modalities, and I think their toxicity will be much less than current, say chemotherapy. And I think we'll have better outcomes, but it will be iterative. Right. I think what we have at the moment is a very good baseline that we know basically it works. There'll be a lot of engineering and a toolbox that we'll need to be able to make these therapies more and more effective. But, you know, the nice thing about it is we have the entire nature, if you like, as a toolbox. You know, there are many genes and many ways of engineering genes in order to make them even more effective than they are now. And I have no doubt that when you combine that with, say, AI and machine learning, we will accelerate the development of these kind of therapies here in the future.
[00:17:11] Speaker A: That's nice. It's also nice to hear you mentioned AI.
I feel as technology has advanced as well as science, there are going to be skeptics on either side that are like, oh, wait, you know, what about this path that's more common, more traditional? So on the heels of that, what are perceived challenges that you have to combat that? I mean, I know you talked in the beginning about, like, using logic to really sit someone down and have them understand your thought process, but what other challenges are you preparing yourself to face?
[00:17:43] Speaker B: Well, there are challenges of things that we just don't know at the moment how to solve, you know, and it will take something that some investigator at some academic institution, institution finds some sort of either interesting molecule or something, and it may not be directly related to gene therapy. They may be working in a completely different area, but has some sort of insight that actually provides us additional levers and handles in order how to address a particular problem. So one problem is solid cancers. We can treat with CAR T cells, liquid cancers quite well, like leukemias and lymphomas and multiple myeloma. But the solid cancer is a little bit different. You know, it is a mass, right.
And when T cells approach those masses, they have a much more difficult time trying to, you know, destroy the tumor. So there's a lot of investigation at the moment of the tumor microenvironment, how to improve the CAR T cells. But that's, that's the cutting edge. I mean, those are the challenges. If we can solve some of those challenges for solid cancers, then I think we have a unique opportunity to treat many people with various serious diseases. But those are some of the challenges I think, and then ultimately, how do we move forward to further reduce the cost? You know, right now we're taking cells out and putting cells back in. There's a lot of effort in terms of short, shortening that process and even just using the vector directly, you know, into the body, that could be the future as well. So there's a number of things that we have to think about on how ultimately the whole gene therapy field will look like in the future.
[00:19:06] Speaker A: Yeah. If you and I, thank you so much for your time.
I always love ending my interviews like this because it's just really nice to hear people's reflection. But if you were to go back in time to the beginning of your journey, whether that be at Johns Hopkins, whether that be at your first company that you started, whether that be your first clinical trial, what would you have told yourself?
[00:19:27] Speaker B: It's hard to make that kind of a comment because it's just been a journey. It's been a journey of learning.
And I wouldn't change anything, to be honest with you, because that's part of the journey, has been that learning.
And as we sort of reach the new hill, we saw an additional vista that we wouldn't have known before reaching that hill. So it's hard to say what would you have known? Because at that time, I didn't approach that first hill, so I couldn't see that next vista, that next opportunity, or that next challenge that I needed to take. And I'm just grateful for the journey, to be honest with you. I wouldn't change anything.
[00:20:08] Speaker A: Thank you for that. It's very clear the way you speak about how you've been on this journey, that that spirit of freedom and curiosity has just naturally led you to so many wonderful places in your career and obviously is going to help shape and impact all these patients across the world. So, honestly, thank you for your time.
[00:20:27] Speaker B: I've been very blessed, and I thank you for your time. I appreciate being able to share some of my journey with you again.
