CAR T-Cell Studies in Autoimmune Diseases Are Proliferating
At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.
At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.
Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.
For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
Complete B-Cell Depletion Is Followed by Full Recovery
“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.
Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.
Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.
In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.
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Greg Deener
cCAR T-Cell Construct Targets Immune Reset
With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.
B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.
However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.
The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.
Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.
Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.
Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.
Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.
“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.
Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
Other Case Series Presented at EULAR
Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:
Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.
Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.
Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented. Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.
August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.
A version of this article appeared on Medscape.com.