Enabling In Vivo CAR-T Therapy Delivery With Vyriad's Stephen Russell

In this episode of Sit and Deliver, host Tom von Gunden and Vyriad Co-Founder and CSO Stephen Russell discuss in vivo delivery of CAR-T cell therapies as an alternative to ex vivo approaches requiring cell harvesting and reinfusion. Russell describes lentiviral vectors delivered in vivo to trigger T cells to attack cancerous tumors. He outlines benefits of the approach, including increased patient convenience, as well as reduced costs across the healthcare ecosystem.

Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader, and as always, your host for the series. Today, I am pleased to be joined by Stephen Russell, who is co-founder and chief scientific officer at Vyriad, a pipeline and therapy development company focused on oncology therapies.

Welcome, Stephen.

Stephen Russell, Co-Founder and Chief Scientific Officer, Vyriad:

Thank you, Tom. I'm excited to be discussing this with you.

Well, I'm certainly excited, and it's a pleasure to have you here. So, let's just go ahead and dive in.

We are going to primarily focus on what people think of as CAR-T-based therapies, immunotherapies for oncology, or immuno-oncology therapies. You can feel free to broaden the scope if you'd like, but that's what I understand we're most likely focused on.

And so, a lot of our audience is probably familiar with the general idea of CAR-T treatments in terms of patients needing to have their cells extracted, engineered, and re-infused. But just to make sure we set a good foundation for the contrast between current methods along that line and what you're going to be describing as happening, in the development areas at Vyriad:

Could you give us a little bit more than a 101 about what actually happens to make those kinds of approaches work today?

Yes. So, in the absence of the ability to deliver the gene directly to the T cells in the living patient, we have to remove the cells from the patient, ship them off to another site where they are genetically modified using lentiviral vectors, which deliver the CAR transgene into the T cells.

There's lot of release testing before they're sent back to the treatment center. And then the patient has to receive a fairly hefty lympho-depleting chemotherapy to essentially make space for the T cells that are going to be re-infused.

And the vein-to-vein time, as they call it, is typically four to six weeks in the real world. And during that time, the patient may need additional chemotherapy to keep the disease under control. And, in fact, unfortunately, some patients die while waiting to receive their engineered CAR-T cells back.

So, it's, logistically, a very problematic approach. And it’s also very expensive for the patient because of all the waiting around that has to happen and because of the cost of the process.

Gotcha. So, what you're going to be describing is what we would call an in vivo approach. Among the key things that it eliminates that you just described would be those trips to centers to have cells harvested, so to speak, and reinfused. And then, obviously, the other burden of the rounds of chemotherapy.

So, tell us about what Vyriad is working on: what it does and how it works to provide an in vivo alternative.

Well, Vyriad is working on a conceptually very simple alternative to that ex vivo system, wherein the lentiviral vector that's used to introduce the CAR transgene to the T cells is delivered intravenously to the patient. And that vector then finds the T cells, genetically modifies them where they live, and that's it. Job done. The T cells are then in position and ready to attack the tumor.

So, it greatly simplifies the current logistically difficult approach and makes it a much better experience for the patient.

Without asking you to give away too many secrets of the sauce from a proprietary science and technology standpoint, but could you go a little deeper? How does it actually work? What’s it doing?

So, good question. And for that, you have to consider how the gene is actually delivered into the T cells.

The lentiviral vector is essentially a viral structure. It's derived from HIV. It has been based on everything we learned about HIV. It has been engineered to carry the CAR transgene into the T cell and to integrate it into the chromosome of the T cell, so that all of the progeny of that T cell are capable of attacking the tumor. It's sort of a living drug.

And as the T cells grow in vivo, they attack the tumor. So, the lentiviral vector is capable of doing this. But in order to do that to the T cell, it has to get in.

And so, the lentiviral vector has an envelope, a lipid envelope. It has a protein core. And then within the core is the genetic material that will be delivered. And within the envelope Is a protein that recognizes and binds to the target cell, is endocytosed into the target cell, and then drives the fusion of the viral envelope with the envelope of the endosome. That delivers the core into the cytoplasm of the targeted T cell.

Now, in the absence of targeting, you have to bring the T cells to the lentiviral vector. The key to our approach is to engineer the surface of the lentiviral vector so that it exclusively recognizes T-cell surfaces — that it's endocytosed exclusively by the T cell, which, by the way, it activates on the way in to wake the T cell up. And then continue, as previously, to deliver the transgene into the chromosome of the T cell.

So, the key to this is really the envelope glycoproteins in the lentiviral vectors, which mediate attachment and then, subsequently, fusion. And what we've done is to engineer them first to remove their ability to recognize cells other than T cells. So, we've sort of wiped the slate clean by engineering that surface glycoprotein so it doesn't interact with other cells in the body.

And we've then equipped it with a binding domain fused to its extreme end terminus, which then interacts specifically with T cell. And the binding domain recognizes CD3, a T cell surface antigen.

As the vector particle binds to the T cell, it sends an activation signal through CD3 and is then internalized via CD3. Whereupon, having deleted its ability to recognize other receptors, we have not compromised its ability to fuse the two membranes that are now attached to each other. And so, the entry into the cytoplasm through fusion occurs efficiently, and the gene is delivered.

So that, in a nutshell, is the targeting approach. It’s to engineer the surface glycoprotein to give it high specificity to T cells so that, when we administer it intravenously, it is not going to transduce germ cells. It’s not going to transduce the cells in the major organs that serve all our vital functions. And it's not going to deliver the CAR transgene into tumor cells, which needs to be avoided.

So, it's a highly specific delivery that we really are focusing on here.

Well, that all sounds good. So, obviously we are envisioning an intravenous method currently. And perhaps that's preferred and the most effective and efficient and always will be.

But should we be envisioning potentially other routes of administration other than IV for getting these therapies into patients who need them?

I think we could do. It’s a really interesting question because there's a big numbers game going on here. When we infuse lentiviral vectors into the bloodstream, we need to infuse close to a trillion lentiviral vector particles per patient. We are sending in a swarm.

And those particles are distributing throughout the body. And those that encounter T cells on their journey are capable of transducing those T cells. So, we are transducing T cells in multiple different locations. And wherever the tumor cells happen to be, there's going to be a nearby lymph node or other lymphoid organ in which we've converted T cells into these living drugs.

So, if we then try and map that onto a local or loco-regional delivery we may or may not be compromising the whole effect. It might be, though, that we could have a subcutaneous depot from which particles enter the bloodstream slowly over a period of time and migrate that way. We could go into the peritoneal cavity, or we could think of other delivery routes that might be equally effective.

We just don't, at this point, have data on those delivery routes to be able to say, oh yes, we're going to move away from intravenous delivery now.

Yeah, fair enough. Thanks for providing at least some view of the landscape of possibility regardless of current state.

Anyway, as you and the folks there continue to work on moving these platforms and therapies forward, are there any particular next-up or front-of-mind problems to solve or challenges to overcome or lessons learned and leveraged, right in front of you and the folks there to move the dial of innovation forward?

Absolutely, and it's down to the numbers game.

So, I just told you we're putting in something in the region of a trillion particles. But we don't want to create a trillion CAR-T cells in the patient. In fact, the typical dose of CAR-T cells that is administered in the ex vivo setting is something in the region of 100 million. And so, that's the target transduction population within the patient.

Why do we infuse a trillion? Because the efficiency of transduction of T cells per particle infused is low. And so, we may have to infuse 1 to 10,000 particles to transduce a single T cell in the patient. In part, that's just because the particles themselves are imperfect. Some of them may bind to a T cell but then fail to complete the entire delivery process.

And so, there's a huge amount of fine tuning that remains to be done in that regard. And so, we're working on every aspect of the biology of these lentiviral vectors in order to tighten the efficiency and thereby reduce the number of particles that need to be infused per patient.

That's going to have a huge impact, ultimately, on the cost of goods. And cost of goods is really a crucial aspect of this because, currently, the cost for the lentiviral vectors that are used to transduce T cells is in the region of half a million dollars per patient. So, bringing that cost down is really a key target.

The other aspect that I think really maps onto that goal very nicely is to work on the manufacturing methodology itself. And our ability to scale that manufacturing methodology, simplify it, simplify the purification of the lentiviral vectors that are going to be infused into the patient: most of our R&D effort is directed at those goals at the moment, thinking of future generations of lentiviral vectors that will be used for in vivo gene therapy applications.

Another aspect that we are working on is to look at different targets because T cells are not the only target in vivo [for which] it would be good to achieve this same integrated transgene, transforming the cell and its future progeny.

And hemopoietic stem cells are obviously front-and-center in that regard because there are quite a few examples now of ex vivo gene therapies along the lines described for CAR-T that have an impact on bone marrow disorders, like thalassemia, sickle cell anemia, severe combined immune deficiency, and so on.

Gotcha. Well, you have already been pointing to the future and looking out over the landscape with your response to that question about what the folks are working on. And you have mentioned some goals. So, if any of this becomes redundant, you don't need to feel free to repeat it. But I like to end these conversations looking out over, especially, the patient experience and the patient outcomes aspect.

And so, [is there] anything else to say? Obviously, there's the elimination of needing to have cells harvested and go to centers to do that process, and the elimination of chemotherapy treatments. But anything else that we should envision that the patient treatment regimen and/or outcomes might look like — or we hope will look like —once these therapies make their way into the market at some scale, which we hope and anticipate that they will.

Well, I think the beauty of this platform is that you can piggyback other advancements into the platform. So, you know, there's a great deal of work going on into how to make the CAR-T cells function more effectively.

At the moment, CAR T-cell therapy is really well developed for hematological cancers. But for solid tumors, it doesn't seem to work so well. And there's a great deal of research going on to why that might be and how to enhance them by introducing additional transgenes alongside the CAR: encoding cytokines, for example, that are going to enhance the function of the CAR in its attempt to kill the tumor cell or which will change the trafficking of the CAR-T cells into the tumor where they need to be to do their job.

And so, all of these types of advances can potentially be incorporated into this approach of direct in vivo.

The other thing to consider is that we have the potential with direct in vivo of expanding the identity of the cell types that we target. In theory, we can go directly into T cells but also into other cell types that can work in concert with the T cells to enhance the antitumor activity. This is something that's much more difficult to think about ex vivo, and it's really an appealing approach in vivo.

So, we may end up with single-shot therapies that really do give long-term, favorable treatment outcomes that are not achievable with the ex vivo approach.

Well, it all sounds wonderful and promising should it all come to fruition. So, Stephen, I'd like to thank you again for joining me to share your perspectives with our Drug Delivery Leader audience. And to that audience, I'd like to say thanks for joining for another episode of Sit and Deliver. And we'll see you next time.

About The Featured Guest

Stephen J. Russell, MD, PhD, is a world-renowned researcher in the field of gene and virus therapy. He combines more than three decades of leadership as a clinician and researcher with extensive experience in all aspects of drug discovery and development.

A board-certified hematologist, Dr. Russell is a co-founder of Vyriad, the Richard O. Jacobson Professor of Molecular Medicine at Mayo Clinic and immediate past President of the American Society of Gene and Cell Therapy. Early in his career, Dr. Russell pioneered novel methods for engineering viral cancer immunotherapies. He was a founder of Cambridge Genetics, a biotechnology company, and the European Society of Gene Therapy. At the Mayo Clinic, Dr. Russell founded the Department of Molecular Medicine and built a comprehensive oncolytic virotherapy program. He has authored more than 400 peer-reviewed research papers and is a frequent speaker at scientific and medical conferences. Dr. Russell received his MD from the University of Edinburgh and a PhD from the University of London.