Dr. Murat Kalayoglu, President & CEO, Cartesian Therapeutics: The Leader in RNA Cell Therapy

DocWire News recently spoke with Murat Kalayoglu, MD, PhD, President & Chief Executive Officer of Cartesian Therapeutics, a company that specializes in RNA cell therapy, a novel class of therapy that combines the best parts of conventional nanoparticle-based RNA therapy with strongest aspects of conventional DNA-engineered cell therapy. Dr. Kalayoglu spoke to us about Cartesian, and a number of clinical programs the company has underway to treat such diseases as multiple myeloma and acute respiratory disease syndrome.

DocWire News: Tell us about Cartesian Therapeutics.

Dr. Murat Kalayoglu: Yeah. So, Cartesian is a pioneer in RNA cell therapy. So, we are a clinical stage biotechnology company based out of Gaithersburg in Maryland. We’re a fully integrated company. In that we do discovery here in-house, we do clinical operations in-house, but we also have our GMP manufacturing facility here and our own quality management systems. That level of integration has allowed us to matriculate assets from preclinical development to clinical development relatively quickly. That we currently have three assets in clinical development, across three different disease categories. And then another handful of three, of preclinical programs that we’re working on in our discovery and translational group.

What is an RNA cell therapy?

Yeah. So RNA cell therapy is a new therapeutic category, that is born out of a marriage between the conventional RNA therapeutics and conventional DNA-based adoptive cell therapy. Conventional RNA therapeutics are basically the COVID vaccines, right? So an RNA molecule is engineered into a nanoparticle and administered into the body directly. And conventional DNA-based adoptive cell therapy is, that your typical conventional CAR Ts for example. Where you have cells, immune cells that are engineered with DNA that integrates into the cell’s genome. What we do is take the best from both of these parents, into this new disease therapeutic category. We take the RNA from the conventional RNA therapeutics and we take the immune cell from the conventional adoptive cell therapy, to create this new therapeutic category called RNA cell therapy. And there’s some distinct advantages of this approach relative to its parents.

And so compared to conventional RNA therapy, RNA cell therapy allows us to be able to use this cell as both a factory for producing as well as a vehicle for delivering a combination of RNA therapeutics, right to the site of disease. So we can be much more precise in terms of how we hone our RNA therapeutics, right to the disease. We also have much less of an issue with immunogenicity. So, one of the big issues with RNA therapies and why they’re so good as vaccines is because they induce the immune system to activate. But that’s a good thing for vaccines. But not a good thing for therapeutics, because then your therapeutic gets cleared up. When you use the cell as a delivery vehicle, immunogenicity is much less of an issue.

Compared to conventional adoptive cell therapies, RNA cell therapy is just safer. Because RNA has a half-life, it has a beginning, a middle and an end. And you can very specifically control the life of your therapeutic inside the body, because RNA doesn’t permanently and irreversibly get integrated into the cell genome. And so as a result, where we have a lot less toxicity, both short-term as well as long-term. The risks of transformation, these cells turning into a cancerous cell are negligible to nil. It’s also a lot less expensive to use these cells in these ways. We also don’t have a cargo limit. So we can theoretically engineer many, many different RNA therapeutics within a single cell and use the cell as the delivery vehicle, right to the site of disease. A new therapeutic category, and we’re quite excited to be right at the cutting edge of it.

What is myasthenia gravis, and what clinical asset does Cartesian have to treat it?

Myasthenia gravis is one of our clinical indications we’re going after, as a representative autoimmune disease. It’s really a classic autoimmune disease, in that pathogenic autoantibodies attack a particular tissue in the body to cause the disease. And in myasthenia’s case, those pathogenic autoantibodies attack the junction between the muscle and the nerve. The neuromuscular junction, and prevent appropriate signaling the muscle and cause muscle weakness over time. And a lot of patients have the localized form of this or it just affects the eyes, it’s called ocular myasthenia. Then there’s a good fraction of patients that have the systemic form, where they’re weak throughout. Before the advent of steroids, a third of patients died as a result of this disease. Even today, the kinds of therapies that are used, these toxic immunosuppressives often cause the side effects that are worse than the disease itself.

So, there’s an urgent need to develop new therapies to address this disease. So what we do is use one of our products, DESCARTES-08, to address this disease. And the way we do it is we engineer these cells, these T cells, with a molecule called the chimeric antigen receptor. A CAR, that targets that binds to a protein that’s expressed in the long-lived plasma cells in the body that produce the pathogenic autoantibodies that go and bind the neuromuscular junction. It stands to reason if we can kill the long-lived plasma cells that are producing these pathogenic autoantibodies, that we can address this disease right at the source and get rid of the disease right at the source. And that’s what these CAR T cells do.

The fact that we’re engineering them with RNA instead of the conventional DNA way of engineering these CAR T cells makes all the difference. Because we can control the life of these cells in the body, they’re a lot safer. And as a result we can go after an indication such as myasthenia, when virtually all CAR T cells out there are relegated to having to target these very end-stage, severe patients with advanced cancer. And the reason is because there’s, they’re often so toxic that it doesn’t make sense from a risk-benefit perspective to use these types of conventional adoptive cell therapies to go after anything other than advanced cancer. By making our therapies safe, we’re able to go after diseases not only in early-stage frontline oncology, but even beyond oncology into autoimmune diseases and other diseases. Within autoimmune diseases, myasthenia is the first one that we’re going after.

Cartesian has two clinical programs in multiple myeloma, tell us about them.

Sure. Now, so multiple myeloma is another disease we’re very interested in. We have two programs that are going after this, this blood-bone cancer. Myeloma is a very difficult cancer to treat and cure. There’s been a lot of work in new therapies over the last decade, there’s a lot of options that patients now have, but virtually every patient will eventually relapse. Our aim, through the use of RNA cell therapy, is to treat the disease early enough, in a way that combines with the other therapies that are available to patients. Such that we eliminate every remnant, every last cell in the body. And you can do that a lot easier in… when the patient has just recently been diagnosed compared to when the patient has the most advanced form of the cancer. It’s true with any disease, and in particular that’s true with multiple myeloma.

So the idea behind our programs is let’s make the therapy safe enough to go after patients when they are diagnosed early on, as opposed to waiting until the very end, right? So the two programs that we have for this indication are DESCARTES-08 for patients with newly diagnosed high-risk multiple myeloma, okay? And these are patients that are recently diagnosed, they undergo their standard of care therapy. And we treat these patients at the end of their standard induction therapy and before their autologous stem cell transplant, to see if we can eliminate every last clone. That clinical trial is underway. A recent addition is a program called DESCARTES-25. The idea behind this program is we can use the cell as the factory for delivering a combination of highly potent antitumor proteins right to the site of disease, where the myeloma cells are.

So these cells are engineered, and they’re mesenchymal stem cells instead of T cells. And they’re off-the-shelf instead of autologous, there’s some differences here. But they’re engineered in order to go after the disease, right where the disease is at. And then just deploy their cargo, a very potent, synergistically-active combination of antimyeloma proteins to right where the myeloma is. So we’re very excited about that, and that’s in patients with advanced myeloma at first. The hope and expectation is that we will eventually move that product into treating patients with early-stage myeloma.

Cartesian’s fourth clinical program is in acute respiratory disease syndrome (ARDS). What is ARDS, and what is the treatment?

The fourth clinical program we have is for respiratory diseases. And in particular, patients with acute respiratory distress syndrome. So ARDS is a relatively common and end-stage respiratory collapse that can be due to both infectious agents, as well as noninfectious agents. Within the world of infection, before two years ago, the majority of cases were due to influenza. And you would have up to 180,000 such cases in the US alone. Now after COVID, the vast majority of patients who suffer from ARDS suffer from it because of COVID. So, it’s a common condition. It’s often what ends up killing you, if you have COVID. Ultimately there hasn’t been a single new treatment that has been approved for ARDS over the last two, even three decades. There’s an urgent need to develop new therapies.

The way we come after this indication is to engineer off-the-shelf, allogeneic mesenchymal stem cells. That are engineered with a combination of DNases that work together to degrade something called NETs, neutrophil extracellular traps. NETs are the sticky webs of DNA that are expulsed by neutrophils in their attempt to control acute inflammation. And so they basically release these gobs of, just think of them as spider webs that are designed to entrap bacterium and viruses. But the problem is they overdo it. And as a result, these sticky webs of NETs serve as the nexus of inflammation. So it stands to reason if you get rid of these, then you could relieve some of the blockage in the alveoli and allow the patient to breathe easier. Then eliminate some of these, some of this thrombosis in the venous system that blocks the blood from flowing freely.

And so that’s what this clinical study is about, using DESCARTES-30 to treat patients with moderate-to-severe ARDS. And hopefully, the kind of safety data and preliminary efficacy data we intend to get will open the doors to be able to use the same product to treat patients with earlier-stage disease. Apropos of our ability to use RNA cell therapy to go after earlier stage indications and beyond oncology, so patients with pneumonia instead of ARDS and even patients with other inflammatory diseases.

What is next for Cartesian? What milestones are expected in 2022?

In 2022 we hope to get some topline data across three of our four clinical programs, which will guide our decision making in terms of what the next steps might be. Yeah, we have preclinical programs that are the next generation of the clinical programs we’re currently in. And we’re right now very focused on execution for clinical trials that are currently ongoing, in order to be able to take a peak at some of the clinical data across our DESCARTES-08 in myasthenia study, across the DESCARTES-08 in the frontline myeloma study, in DESCARTES-30 in ARDS. Potentially even towards the end of the year, take a peak at some of the data for DESCARTES-25 in myeloma as well. So, that clinical peak will inform the next set of decisions from a strategic perspective and also inform what kind of programs we want to prioritize from a preclinical development perspective.

Any closing thoughts?

I am excited to be a part of this, this adventure in cell and gene therapy in general and RNA cell therapy in particular. That the platform technology that we’ve built, that we’ve coined the RNA Armory, is capable of generating more cells than has ever been historically possible. Engineering them with RNA in, that expresses itself over an extended period of time. And so, it’s an exciting time to be a part of this field and pioneering this new class of therapies. Because in 2022, the technology and resources are available to be able to really make some cutting edge breakthrough technologies accessible to a large number of patients within the world of cell and gene therapy.