Hematologist oncologist Miloš Miljković, MD, joined Cartesian Therapeutics as chief medical officer (CMO) in September 2021 from the National Cancer Institute (NCI) to do what he does best—develop and execute clinical programs—to help the RNA cell therapy company re-establish its stride in autoimmunity following the COVID-19 pandemic.
“CAR-Ts have become a big thing now in the last year or so in autoimmunity, but Cartesian, who’s been the leader there, started the first myasthenia gravis trial in 2019,” Miljković told Inside Precision Medicine. “After treating the first three patients, COVID struck, and things slowed down. As things were picking up again, I came on board to take the CMO responsibilities… to further develop Descartes-08, the lead product, in myasthenia gravis and do a big phase II study.”
Miljković and Cartesian are now at the forefront of cell therapy for autoimmunity. They have made much progress on Descartes-08, an mRNA-engineered chimeric antigen receptor T-cell therapy (mRNA CAR-T) product candidate that targets the B-cell maturation antigen (BCMA). Cartesian recently received top-line data from a completed double-blind, randomized phase IIb study for Descartes-08 in myasthenia gravis, which received—a Regenerative Medicine Advanced Therapy (RMAT) designation in May this year for expedited approval—and is preparing for a phase III trial. Other indications, such as lupus and pediatric autoimmune diseases, are also undergoing testing with Descartes-08.
This week, the U.S. Food and Drug Administration (FDA) granted Descartes-08 Rare Pediatric Disease Designation to treat juvenile dermatomyositis, a condition characterized by idiopathic inflammatory myopathy, muscle weakness, and other issues caused by presumed autoimmune dysfunction. Severe and potentially fatal diseases affecting fewer than 200,000 Americans, primarily children under the age of 18, are eligible for the Rare Pediatric Disease Designation and Voucher Program. Therefore, if the marketing of Descartes-08 for juvenile dermatomyositis receives approval, Cartesian could potentially receive a priority review voucher, which they could then use to request a priority review of a different product’s marketing application in the future.
Transient, diluting CAR-Ts
The primary distinction between Cartesian and competitors such as Kyverna Therapeutics is that the former employs an mRNA approach to perform a “transient modification” of T cells. When requiring genome modification, leukocytes are extracted from a donor’s blood using specialized apheresis and then transfected with lentiviral and integrating vectors to generate the CAR-Ts. A single injection reintroduces the cells into the patient, necessitating genotoxic conditions to eliminate resident leukocytes and enable the CAR-Ts to survive and proliferate in vivo.
However, Cartesian’s mRNA approach expands the leukopak ex vivo to produce billions of leukocytes, which undergoes RNA engineering (via an undisclosed non-viral method) to produce Descartes-08 cells. One of the advantages of this mRNA approach is that there’s no genomic integration, so there’s no risk of insertional mutagenesis, and the infused cells eventually get diluted out.
“[Descartes-08] cells are not permanent, which is a downside in oncology because in oncology you need [the CAR Ts] to circulate and survey permanently—that’s where the permanence of CAR T cells has a benefit, explained Miljković. “In autoimmunity, you want the exact opposite. You want to get rid of only the auto-reactome, the self-reacting antibodies.”
Miljković continued, “When you look at cancer and cancer antigens, most of the cells with your [CAR T] target will be the cancer cells. While some bystander cells may exist, the overwhelming presence of cancer makes them your primary target. In autoimmunity, that’s not the case—most cells will be bystander cells. The BCMA-positive cells are plasma cells, mostly in the gut and lungs, which make antibodies in reaction to outside pathogens. Because normal lymphocytes have no physiological reason to go there, Descartes-08 doesn’t touch them. Instead, Descartes-08 targets the bone marrow. We’ve known since the 1980s that the pathogenic plasma cells in myasthenia gravis reside in the bone marrow.”
Also, because there is no genotoxic conditioning, the safety profile has been promising regarding the lack of dose-limiting toxicity events and cytokine release storms. The primary safety concern has been infusion-related reactions, which tend to resolve within two days of infusion.
“There are many pediatric autoimmune diseases that right now your only treatment options are broad immunosuppression that’s chronic, and for somebody young, that chronic administration makes a huge difference,” said Miljković. “With Descartes-08, it’s six once-a-week doses, and we see durable benefits. Adults see benefits up to and past a full year.”
Of the seven original myasthenia gravis patients treated with Descartes-08, four still have an ongoing response that has lasted over a year, two had responses crash out at about a year, and a third made it up to a year and a half until losing the response. According to Miljković, the worst-case scenario is that a patient would need to get six doses of Descartes-08 once a year, which is still much better than ongoing chronic immunosuppression.
An outpatient procedure
After production, the team at Cartesian aliquots Descartes-08 cells for serial dose administration. Miljković explained that the team at Cartesian conducted an open-label study demonstrating that the optimal dosing strategy is to infuse Descartes-08 once weekly every six weeks. So, on the one hand, the patient has to undergo six procedures with the Cartesian approach. Still, the upside is that since there’s no requirement for genotoxic conditioning, the procedure is amenable to the outpatient setting.
“Chemotherapy is a big concern in the pediatric population, so there are very few pediatric patients with autoimmune disease where you would even think about chemotherapy,” said Miljković. “We don’t use chemotherapy. We can also administer [Descartes-08] in an outpatient setting, which has a huge impact on the family, particularly when a child is admitted to the hospital and must stay there for weeks, missing school and numerous activities. You don’t need to cut out a month or two of your life to dedicate yourself to that.”
Another factor that makes Cartesian’s approach suitable for the outpatient setting is its ability to handle biohazard control issues. Miljković said, “To prepare the cells, you don’t need to use a hood; it can be done literally at the bedside in an outpatient clinic. You don’t need a bone marrow transplant facility to do it.”
If Descartes-08 goes to market, Cartesian may have a few advantages over competitors using lentiviral vectors, which can be a major manufacturing bottleneck. Miljković said that thanks to all the developments around the mRNA vaccines, there have been major manufacturing advancements. The mRNA engineering and ex vivo propagation method may also be less expensive because patients don’t have to stay in the intensive care unit or be monitored for longer periods.
“The direct costs are lower because it’s mRNA and not a lentiviral vector, and the indirect costs are lower because the administration setting is different and there’s not a lot of monitoring—one hour after infusion in the outpatient center, if they’re fine, the patients can go home.”
While things look promising for Cartesian, they’re not resting on their laurels with Descartes-08. At the same time, Cartesian is working on their next-generation BCMA CAR T, Descartes-15. Miljković said it is ten times more effective than Descartes-08 and is currently in a first-in-human study for people with multiple myeloma. They hope to also test it in people with autoimmune diseases like lupus and rheumatoid arthritis in the future.
