Safety and Tolerability of BCMA-Directed mRNA CAR T-Cell Therapy in Multiple Myeloma and Autoimmune Disease

Descartes-08 is an mRNA-engineered chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA). We hypothesized that replacing the traditional integrating vectors characteristic of CAR T with mRNA would improve the safety profile of CAR-T by reducing risk of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and secondary malignancies. These advances would enable outpatient administration without intense or prolonged monitoring (Lin, 2021), while the use of RNA could eliminate the need for preconditioning chemotherapy. In addition to multiple myeloma (MM), targeting BCMA may also result in clinical benefit to patients with autoantibody-associated autoimmune disorders such as myasthenia gravis (MG) and systemic lupus erythematosus (SLE), where pathogenic BCMA-positive plasma cells are known to be key drivers of disease (Granit, 2023).

We tested Descartes-08 in patients with relapsed/refractory (r/r) MM (NCT03448978), high-risk (hr) MM who experienced residual disease after induction therapy (NCT04816526), and patients with generalized MG requiring immunosuppression (NCT04146051). The studies were supported by Cartesian Therapeutics and the NIH (NCI and NINDS).

A total of 91 patients received at least one dose of Descartes-08 across the studies. Patients with r/r MM received escalating doses of Descartes-08 with (n=30) and without (n=15) lymphodepletion chemotherapy. The median number of cells infused was 6.01 (95% confidence interval 4.19-7.83) x10⁹. Patients with hr MM (n=13) received six twice-weekly infusions of Descartes-08 over three weeks in an outpatient setting and without lymphodepletion chemotherapy, with median 16.2x10⁹ (range 5.9-27.4x10⁹) cells infused. Patients with MG received three dose-escalated (n=3), or six doses at the maximum tolerated dose (52.5x10⁶ cells/kg) twice-weekly (n=4), once-weekly (n=26) or once-monthly (n=1) with median 18.9x10⁹ (range 2.4-42.5x10⁹) total cells infused outpatient and without preconditioning chemotherapy.

The most common AEs assessed by investigators possibly related to Descartes-08 were fever (40%, of which 6% G2, 3% G3), nausea (30%, 10% G2, 1% G3), myalgia (29%, 14% G2, 2% G3), fatigue (22%, 8% G2) and headache (20%, 8% G2). Additional Grade 3 AEs were diarrhea (3%, all in patients with r/r MM after lymphodepletion chemotherapy), HSV reactivation (1%, in a patient with MG on additional nonsteroidal immunosuppression), thrombocytopenia (1% G3 and 1% G4, both in hr MM) and rash (1%). Six patients (7%) experienced treatment-related serious adverse events: 2 infusion-related reactions, 2 fevers, 1 each rash and HSV reactivation, all of which resolved completely and with no sequalae.

All fevers occurred within 4-12 hours of infusion and resolved within 24-48 hours with no intervention other than acetaminophen or nonsteroidal anti-inflammatory drugs. There were no instances of ICANS reported, and the only hematologic toxicities were reported in participants with MM.

Clinical experience to date supports administration of mRNA CAR-T therapy in an outpatient setting and without lymphodepletion chemotherapy. Further clinical development of Descartes-08 is focused on adult and pediatric autoimmune disease, including MG (NCT04146051) and SLE (NCT06038474).

Miljkovic:Cartesian Therapeutics: Current Employment, Current equity holder in publicly-traded company. Asch:Servier: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Boccia:Cartesian Therapeutics: Research Funding. Berdeja:2 Seventy Bio; Abbvie; Amgen; BMS; C4 Therapeutics; Caribou Biosciences; CARsgen; Cartesian Therapeutics; Celularity; CRISPR Therapeutics; Fate Therapeutics; Genentech; GSK; Ichnos Sciences; Incyte; Janssen; Juno Therapeutics; K36 Therapeutics; Karyopharm: Research Funding; AstraZeneca; BMS; Caribou Biosciences; Galapagos; Janssen; K36 Therapeutics; Kite Pharma; Legend Biotech; Pfizer; Roche; Sanofi-Aventis; and Takeda: Consultancy; Janssen: Honoraria. Altuntas:Yildirim Beyazit University Dept of Internal Medicine & Hematology: Current Employment; Transfusion & Apheresis Science: Current Employment; World Apheresis Association (WAA): Ended employment in the past 24 months; Ankara Oncology Training & Research Hospital: Membership on an entity's Board of Directors or advisory committees; Ankara Oncology Training & Research Hospital Hematology & BMT Unit: Membership on an entity's Board of Directors or advisory committees; Excellence Center of Clinical Trials: Membership on an entity's Board of Directors or advisory committees. Howard:Cartesian Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion, argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings or travel, Research Funding; Biologix Pharma, F. Hoffmann-LaRoche, Amgen, Immunovant, Merck EMB Serono, NMD Pharma, Regeneron Pharmaceuticals, Sanofi, Toleranzia, UCB BIosciences: Consultancy. Vu:Cartesian Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion/AstraZeneca, argenx, Ra/UCB, Horizon/Viela Bio, Janssen/Momenta, Immunovant, Regeneron, Dianthus: Research Funding; Alexion, argenx, UCB: Honoraria. Myers:Cartesian Therapeutics: Research Funding. Chahin:Cartesian Therapeutics: Research Funding. Mozaffar:Cartesian Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion, Amicus, Annji, argenx, Astellas Gene Therapy, UCB: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria; ML Bio, Sanofi, Spark Therapeutics, Valerion: Research Funding; Horizon Therapeutics, Maze Therapeutics, Momenta: Consultancy; Sarepta, Applied Therapeutics: Membership on an entity's Board of Directors or advisory committees. Jewell:Cartesian Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kurtoglu:Cartesian Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Descartes-08 is an investigational BCMA-directed mRNA CAR T-cell therapy not approved for commercial use in any jurisdiction.