When Robin Pettypiece was accepted into a first-of-its-kind clinical trial for myasthenia gravis (MG) in 2022, she was excited and a little apprehensive. She was excited because the phase 1b/2a trial, sponsored by Cartesian Therapeutics, was investigating the safety and preliminary efficacy of Descartes-08 chimeric antigen receptor T cells (CAR T cells), a novel treatment for MG, and nervous because she had to stop the intravenous immunoglobulin (IVIG) treatment, a concentrated solution of antibodies derived from blood plasma donated by healthy volunteers, that had helped her manage her disease for almost 14 years.
Pettypiece was diagnosed with MG in December 2009 at age 44. After asking the doctor to write the name of the disease on a sticky note, she began searching for a neuromuscular specialist. Before she could find one, however, her condition deteriorated drastically. She had debilitating fatigue and difficulty speaking and swallowing. “I went downhill quickly, and things were going haywire,” she says. “My face was drooping, and I slurred my words. People I interacted with through my sales job thought I was drunk.”
She was hospitalized for 10 days in January 2010 as doctors tried to stabilize her condition. She was treated with high doses of steroids and plasmapheresis, a process that removes MG-associated antibodies from the blood—either acetylcholine receptor or muscle-specific kinase antibodies—and then infuses the filtered blood back into the patient. Four months later, Pettypiece returned to the hospital for thymectomy, a surgery to remove the thymus gland, which produces acetylcholine receptor antibodies.
Surgery was followed by two more hospital stays for plasmapheresis in attempts to control her symptoms. Finally in August, Pettypiece met with a new neurologist, who weaned her off steroids and prescribed azathioprine (Imuran), an immune suppressant that disrupts the creation of DNA molecules, and IVIG. The antibodies may help mitigate the immune response and can temporarily improve muscle strength and reduce MG symptoms.
IVIG therapy every two weeks stabilized Pettypiece's symptoms for years. Then in 2022, she had to look for a new neurologist after hers died unexpectedly. During her search, she saw an educational webinar about the CAR T-cell trial and decided to apply.
CAR T-cell therapy is best known for treating cancers like leukemia, lymphoma, and multiple myeloma. The immunotherapy takes patients' T cells, which are part of the immune system and can identify and destroy invading pathogens or tumor cells, and programs them to recognize proteins of interest to treat disease.
To target proteins of interest, T cells are collected from blood using leukapharesis (a process similar to dialysis), reprogrammed in a laboratory, and then given back to patients. In traditional CAR T-cell therapies, the reprogramming is achieved by genetically modifying the T cells' DNA. This DNA-based reprogramming means the T cells continue to recognize their target after they divide. As T cells double with each division, the presence of more and more cells that react to their target can result in a significant immune reaction that can lead to a cytokine storm (fever, fatigue, nausea, and swelling) that can be life-threatening. For this MG trial, researchers found a way to modify the CAR T cells using messenger RNA. Because the effect of the RNA in the T cells is temporary, and the CAR activity does not persist after cell division, the researchers were able to control the extent of the immune response, which improved the treatment's safety. “In the Cartesian study, T cells were programmed using mRNA, which allowed us to regulate how much the CAR T cells can attack their target so there is a lower risk of a severe inflammatory response,” says Volkan Granit, MD, a researcher at the University of Miami.
Over six weeks starting in March 2023, Pettypiece and 13 other participants with MG each received an infusion once a week. Side effects included high fever, bone chills, and headaches, all of which stopped within 12 hours of each infusion. After those six weeks, Pettypiece returned for a few follow-up appointments until the trial ended in March 2024.
Since her last T-cell infusion in March 2023, Pettypiece's fatigue, weakness, and trouble swallowing and breathing have been manageable. She has not had to resume IVIG treatment. “I feel that alone made the trial worth it,” says Pettypiece, who is now 59 and lives in St. Louis. For the first time in more than a decade, she says, she had days when she forgot she had the disorder. “But I believe the effect is wearing off, and I'd like to get reinfused.” While the therapy is currently available only through a clinical trial, she hopes it will be approved in the near future.
In the 1b/2a trial, Descartes-08 appeared to be safe with tolerable side effects, and participants experienced clinically significant reductions on MG severity scales up to 12 months after their last infusions. Other researchers are now looking at ways to use DNA to deliver CAR T-cell therapy safely to people with MG, says James F. Howard Jr., MD, FAAN, a researcher on the Cartesian study and professor of neurology and medicine at the University of North Carolina at Chapel Hill. “CAR T-cell therapy could be transformative and a better choice than current therapies for some patients with MG.”
Data from a phase 2b trial of Descartes-08 are expected soon. At that point, Dr. Howard says, he and the other researchers will analyze the results and decide whether to continue with the next stage. He and other investigators are grateful for clinical trial participants like Pettypiece. “They enable us to move the process forward,” he says.
