Innovating Reversible Cell Therapies With RNA
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In recent years, the field of DNA-modified cell therapies has experienced clinical advancements in patient outcomes specifically in late-stage cancer patients. Permanent changes to the genetic compositions in patients’ cells may lead to toxicities such as cytokine release syndrome, or the uncontrollable proliferation of DNA-modified cells. To address the irreversibility and lack of predictability of DNA-modified cell therapies, Cartesian Therapeutics is developing a range of RNA-modified allogeneic and autologous cell therapies in autoimmune, oncologic and respiratory disorders.
In this interview, Murat Kalayoglu, MD, PhD, president and CEO of Cartesian Therapeutics discusses the company’s efforts to develop RNA-modified cell therapies that expand past oncology. Dr. Kalayoglu also provides his predictions for the nascent field of cell therapy, and clinical milestones we can expect to see in the coming years.
Q: Can you tell us about the history and origins of Cartesian Therapeutics and its technology?
A: Cartesian was founded in 2016 with a mission to develop potent, yet safer, cell therapies initially for the treatment of multiple myeloma. The motivation to innovate novel cell therapies for this rare form of blood cancer was born out of shared experiences between myself and the other founders, chief scientific officer Dr. Mike Singer and chief operating officer Dr. Metin Kurtoglu. Several of our friends and family members have been diagnosed with multiple myeloma, and we recognized first-hand the need for treatment for this incurable disease.
We originally licensed chimeric antigen receptor technology (CAR) T-cell therapy from the National Institutes of Health (NIH) as a unique way of targeting B-cell maturation antigens (BCMA), a critical part of the disease pathway of multiple myeloma. CAR T-cell therapy is a form of immunotherapy in which a patient’s own T cells, a type of immune cell, are modified in a laboratory to bind to cancerous cells. We investigated the potential to engineer these cells with RNA instead of DNA to overcome the limitations of conventional DNA-engineered CAR T-cell therapies.
What began as a focused effort exclusively on multiple myeloma has morphed into a technology platform that we recognize has broad applications beyond oncology. Currently, Cartesian is a fully integrated RNA cell therapy company with multiple cell therapy candidates in clinical trials. Our cell therapies target not just cancer, but also autoimmune disease and respiratory disease. We plan to move forward into additional disease categories in 2022.
Q: How is RNA cell therapy different from DNA cell therapy? What benefits does this bring?
A: In conventional cell therapy, scientists modify the DNA in cells with irreversible, permanent changes at the level of the gene. Each daughter cell produced from a DNA-modified cell is identical to the parent cell, and genetic coding errors may result in the replication of cancerous cells.
DNA-modified cell therapies raise other safety concerns when introduced into the patient. They begin to proliferate when encountering a target antigen and can often proliferate out of control if any semblance of the target antigen is detected. They may cause toxicity and an unwanted inflammatory immune response known as cytokine release syndrome. These adverse effects of DNA cell therapy are harmful for patients already suffering from the debilitating effects of their disease. And while it often makes sense for a patient with an advanced, late-stage cancer to take the risk of encountering these toxicities, it often doesn’t make sense to do so with earlier-stage cancers or conditions outside of oncology.
Our philosophy is to expand cell therapy beyond the most advanced cancers, and we believe using RNA instead of DNA will allow us to make reversible, controllable changes inside cells. Because RNA has a defined half-life, RNA-modified cells are more predictable in the bodies of patients. The changes reflected in RNA-modified cells do not integrate irreversibly into the genome but may last long enough to produce therapeutic proteins without the toxicities common to conventional cell therapy.
In addition, conventional cell therapies require difficult-to-source laboratory equipment or biologically active products such as GMP-grade viral vectors to produce the DNA-modified cells. RNA cell therapy does not require as complex of equipment and allows us to enter the clinic more quickly at a lower cost.
Q: Can you tell me a bit about Cartesian’s RNA Armory® technology and the work being done at the company’s GMP manufacturing facility?
A: At Cartesian, we are developing an entirely new manufacturing platform that we’ve now coined the RNA Armory®. The RNA Armory® is a cell-based combination therapy platform that allows us to use a cell as both a vehicle for delivering as well as a factory for producing a combination of RNA therapeutics. Through the RNA Armory®, we can simultaneously engineer multiple RNAs directly into the cell, enabling us to accurately target the site of disease. These cells are then able to secrete not just one, but multiple RNA therapeutics in the form of secreted proteins right at the site of disease. Because RNA-modified cells lose functionality over time, we can control their effectiveness against the target antigen more precisely than DNA-modified cells that can proliferate unpredictably.
We integrated our manufacturing in-house at our headquarters in Gaithersburg, Maryland, to optimize research, development and supply chain and manufacturing. We believe the platform itself can work with various types of cells, but there are two main areas of focus right now in the clinic: T cells and mesenchymal stem cells (MSCs).
Q: Cartesian is taking cell therapy beyond oncology. Tell me more about the programs in myasthenia gravis and acute respiratory distress syndrome (ARDS).
Myasthenia gravis is a chronic autoimmune disorder in which autoantibodies destroy the communication between nerves and muscles, resulting in neuromuscular weakness. We are developing Descartes-08, a T-cell therapy that targets BCMA. Our rationale for targeting BCMA stems from the fact that long-lived, diseased plasma cells, along with the autoantibodies they produce, typically express BCMA in myasthenia gravis patients.
Descartes-08 is our first-generation autologous cell therapy to combat myasthenia gravis. Our scientists collect and modify a patient’s own T cells using the RNA Armory® to produce redirected (CAR-T) cells. Clinicians then reinfuse the T cells back into the patient’s body over the course of several treatments. Our hope is that Descartes-08 may destroy the very cells that produce the autoantibodies. We recently reported positive results in the first cohort of myasthenia gravis patients dosed with Descartes-08 and have escalated the treatment to an expansion cohort.
We are also developing Descartes-30, our targeted second-generation MSC therapy for patients with moderate-to-severe ARDS. Descartes-30 is an allogeneic (i.e., off-the-shelf) cell therapy currently in Phase 1/2a clinical trials. Our team of scientists harvests stem cells from healthy donors and engineers two different enzymes into them that work synergistically to degrade neutrophil extracellular traps (NETs), a key driver of inflammation and clotting in patients with ARDS. RNA-modified cells are then infused into patients. Our belief is that the degradation of NETs using Descartes-30 may alleviate the burden of ARDS by clearing alveoli and vessels in the lungs.
Q: The company also has a clinical program in multiple myeloma – can you tell me more about this drug candidate and the ongoing clinical study? How does this compare to conventional treatments for multiple myeloma?
A: We are currently testing two different CAR T-cell therapies, Descartes-08 and Descartes-11, to target BCMA-expressing cancer cells in patients with multiple myeloma. Descartes-08 and Descartes-11 vary in their activations and the way in which they bind to BCMAs. We plan to test both Descartes-08 and Descartes-11 in the clinic to determine which one produces more efficacious results in patients with multiple myeloma, advancing the better performing therapy into late-stage clinical trials.
While other cell therapies investigate the potency of treatments in later stage multiple myeloma patients, Descartes-08 and -11 are focused on patients with newly diagnosed multiple myeloma. Multiple myeloma is an incurable disease characterized by relapses that are treated with effective drugs until the patient is in remission. As the disease progresses, the remission period becomes shorter and shorter after each relapse.
Our hypothesis is to develop potent yet safer RNA-modified CAR T-cell therapy for use in the early stages of multiple myeloma. We hope our RNA cell therapy candidates may be combined with other effective drugs at the beginning of a patient’s treatment regimen to eliminate any remnant of the disease during the first line of therapy. Both Descartes-08 and Descartes-11 have been well-tolerated from a safety perspective in Phase 1 clinical trials and are both being tested in Phase 2a studies in patients with high-risk, newly-diagnosed multiple myeloma.
Q: What can we expect for the future of RNA cell therapy in the industry and for Cartesian?
A: We are hopeful for the future of RNA cell therapy. We do not foresee extensive limitations in the kinds of combinations of therapeutics that RNA cell therapy can provide to patients, a challenge that plagues conventional DNA-modified cells. RNA-modified cells have the potential to integrate complex therapeutic combinations. The potential synergistic efficacy and sheer number of combinations may allow clinicians to target the disease precisely and through multiple mechanisms simultaneously.
Q: Why do you think there has not been greater interest in the development of RNA therapy so far? Is this set to change?
A: The main limitation for investigating RNA cell therapies occurs when institutions do not have the capacity to manufacture high quality products at large quantities. Since cells lose function over multiple rounds of proliferation, patients must be dosed with a larger number of cells, and often with repeat-dosing. Institutions and companies must have the capability to scale up high-quality cells, and efforts have failed in the past due to limited manufacturing capabilities that inhibit the quantity of cells produced. We hope more laboratories streamline their manufacturing processes to investigate RNA cell therapies and their potential to help patients across a variety of disease states.