by Ditsa Keren

Exploring RNA-Based Oncology Treatments With Cartesian Therapeutics

Exploring RNA-Based Oncology Treatments With Cartesian Therapeutics
Cartesian Therapeutics is a fully integrated, clinical-stage biopharmaceutical company developing novel cell and gene immunotherapies to treat cancer and autoimmune diseases. In this interview CEO Dr. Murat Kalayoglu discusses the uniqueness of RNA cell therapy and its potential to completely eliminate cancer once and for all.

Please describe the company’s story, mission, and goals. What sparked the idea, and how has it evolved so far?

Cartesian was started in 2016 with the hope and expectation that we could develop an effective, yet safe, treatment for patients with early-stage cancer. At the time, we were focused on multiple myeloma. We set out to discover and develop a technology platform that could address patients who were early in their treatment paradigm.

My partner Mike Singer (CSO at Cartesian Therapeutics) and I have family members who have been affected with multiple myeloma. Our analysis of the available technologies at the time showed that in order to drastically impact patient survival and quality of life, we would need to develop a treatment that was both potent and safe enough to be able to treat a patient when they were first diagnosed with the disease.

Before founding Cartesian, Mike and I had been involved in several different startups in healthcare, information technology, and drug development. We ended up realizing that the intersection of RNA therapies and cell therapy was an area where we could make a real impact.

Unlike the conventional cell therapies, which are all geared towards the permanent, irreversible manipulation of the cell at the genomic level, Cartesian’s engineering platform, called the RNA Armory℠, uses RNA to modify cells as opposed to DNA. The RNA Armory℠ is not making an irreversible change, but a time-controlled change.

In a conventional DNA-based engineering method, a modified cell encounters its target in the body and starts to divide. The daughter cells look identical to the parent cells and as a result, the cell can proliferate out of control, which often leads to complications such as cytokine release syndrome, neurotoxicity, increased risk of infection, and mutagenesis.

Long-term risks, as well as short-term toxicities, are almost synonymous now with conventional cell therapies. Fundamentally, this is attributed to the fact that these cells are changed at the genomic level – at the level of the DNA.

We view our unique RNA-based cell therapies as having a built-in biological pharmacokinetic half-life, because when the daughter cell divides, the RNA is not perpetuated indefinitely from one cell to its progeny. The RNA Armory℠ produces effective therapies because the RNA is still encoding for the desired proteins, but we can control the cell and ensure it doesn’t proliferate out of control and lead to toxicities and other long-term risks.

We felt that the field of RNA cell therapy was promising but nascent. We weren’t seeing meaningful work being done to bridge cell therapy with RNA therapeutics. We jumped into developing RNA cell therapies with the hope and expectation that we would first focus on a single indication, in oncology, specifically in newly-diagnosed patients with multiple myeloma. Over the years, that effort morphed into applying RNA cell therapies beyond oncology.

Today, in 2021, we are targeting not just the first RNA cell therapy for frontline cancer, but the first RNA cell therapy for an autoimmune disease, called general myasthenia gravis, and the first RNA cell therapy for acute respiratory distress syndrome (ARDS).

Looking forward, we hope to broaden the depth and scope of our approach by targeting other indications with more and more combinations of engineered RNAs.

In a nutshell, what exactly is RNA cell therapy?

The larger field is called gene and cell therapy. Gene therapy means that a specific DNA is encapsulated within a nanoparticle or other vector and injected into a patient to try to make a permanent change to the patient’s DNA. This has been applied to some severe diseases, such as hemoglobinopathies and severe combined immunodeficiency. Conventional RNA therapy also falls within the field of gene therapy because the RNA is injected directly into the body and is expected to be taken up by the patient’s cells.

A parallel track to gene therapy is cell therapy, in which a cell is modified in the lab with RNA or DNA, and then introduced back into the body. This can be done using both autologous, or the patient’s own, or allogeneic, or another person’s, cells. At Cartesian, we use RNA, as the modifier in our cell therapies, not DNA. RNA cell therapy has some very powerful and distinct advantages over conventional cell therapy, and we are pioneering this subfield of adoptive cell therapy.

RNA has been in the headlines recently because of the COVID vaccine. Would you say that’s an example of this kind of technology?

People often talk about conventional RNA therapeutics as the direct injection of RNA into the body in the form of an encapsulated nanoparticle or another vector. For us, the carrier is a living cell, which can overcome some of the issues around immunogenicity associated with these vectors.

The COVID vaccines are a typical example of conventional RNA therapeutics; they encapsulate RNA within a nanoparticle that gets taken up by cells. If you inject it on the skin in the form of a vaccine, the RNA makes its way inside the cells and starts to translate into proteins.

The problem with conventional RNA therapeutics, in general, has been the fact that the nanoparticle that carries the RNA is often very immunogenic, meaning it induces an immune response. That’s what makes the COVID vaccines so effective, but this can represent a problem in disease treatment.

Also, these nanoparticles get cleared up quickly so there may not be sustained clinical benefit over an extended period.  Redosing may not be as effective due to recognition by the immune system of the nanoparticles.

The challenges can be overcome by first modifying cells, either from the patient or from a healthy donor, with RNA outside the body, then introducing the modified cells into patients. The modified cell can then secrete these encoded RNA proteins for a longer period, evade the immune system, and be programmed to target the relevant tissue to deliver cargo directly to the sight of disease.

At Cartesian, we have the ability to modify cell therapies with not just one or two but three or more different RNA therapeutics within the cell, which is being used both as a vehicle to deliver these therapeutics and as a factory for making them.

What can you tell us about your technology?

We’re a clinical-stage biotechnology company. We have three assets currently in development:

  • Descartes-08 is targeting myasthenia gravis and multiple myeloma.
  • Descartes-11 is also targeting frontline multiple myeloma.
  • Descartes-30 is targeting acute respiratory distress syndrome (ARDS).

Descartes-08 and Descartes-11 are autologous therapies or modified T cells from the patient’s own body. They are engineered with a redirecting molecule called a chimeric antigen receptor (CAR) that targets one of the most fundamental receptors in autologous plasma cells and myeloma cells, called the B-cell maturation antigen. It’s an autologous therapy and it’s a first-generation therapy because we’re manipulating these with a single CAR.

The second-generation therapy is highlighted by Descartes-30, which is a totally different type of cell: this uses a human mesenchymal stem cell that is derived from healthy donors and engineered with two therapeutic proteins that work synergistically to degrade a fundamental pathway in acute respiratory distress syndrome as well as a whole slew of autoimmune and cardiovascular diseases.

The third generation of therapies that are currently in preclinical development is manipulating both autologous and allogeneic cells with three or more targeting proteins and therapeutic proteins.

These are some of the most complex therapies ever developed. These highly-engineered and sophisticated treatments can be brought together within a living cell to both target these therapies and produce them within the body over an extended period. We hope that at least some of these assets will show promising data and get commercialized over the next several years.

How is this different from existing oncological treatment?

Traditional drug development for cancer therapeutics can be time-consuming and taxing. Historically, a researcher would need to identify a single drug, test the compound in preclinical and in vivo models, receive approval from the FDA to use the compound in humans, measure the safety of the compound in healthy volunteers, and only then test the efficacy of the compound in the patient population intended to be treated.

Once a single compound has been tested and approved, a researcher must then follow the same approach in parallel for multiple therapies together, also known as combination therapies. The length of time and capital it takes to test some of these combination therapies, both pre-clinically and clinically, is astoundingly long and expensive.

What we’ve developed through the RNA Armory℠ is a cell-based combination therapy platform. By engineering one cell with multiple therapeutics, we can rationally choose our targets and combine them within a relevant cell type to see how a particular combination of therapies is going to work for a particular disease.

Cell therapy, in general, and our approach in particular, lends itself to the ability to measure some of these more nuanced hypotheses around combination therapy in ways that a traditional approach to targeting these diseases is not able to do.

How do you think this could become the standard of care in the future?

Biotech is defined by the success of data generated. If a therapy works particularly well and if it’s safe, it is adopted and used, displacing existing therapies.

The therapeutics currently being developed can potentially be either standalone therapies or used in combination with the existing standard of care. The fact that they’re so differentiated in their mechanism and how they solve a problem within a given patient population certainly suggests the potential to become standard of care at some point.

How do you envision the future for oncology patients?

I think the future is bright for patients in general. When comparing therapies in development today versus 10 years ago, five years ago or even two years ago, the rate of development of therapies is just amazing. Cell therapy brings together disparate aspects of drug development to create powerful combination therapies.

As we learn more about how to engineer cells with more and more complexity, we can keep pushing the boundaries and pioneering combination therapy. So I think the future is very bright for patients.

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About Author
Ditsa Keren
Ditsa Keren

Ditsa Keren is a technology blogger and entrepreneur with a strong passion for biology, ecology and the environment. In recent years, Ditsa has been specializing in technical and scientific writing, covering topics like biotechnology, algae cultivation, nutrition, and women's health.

Ditsa Keren is a technology blogger and entrepreneur with a strong passion for biology, ecology and the environment. In recent years, Ditsa has been specializing in technical and scientific writing, covering topics like biotechnology, algae cultivation, nutrition, and women's health.