CAR-T stands for “Chimeric antigen receptor T cell (CAR-T) therapy”. Many studies have demonstrated the safety and effectiveness of CAR-T cell therapy in oncology, particularly in hematological malignancies. However, there is growing evidence about the therapeutic utility of CAR-T in autoimmune illnesses. Autologous CAR-T cell therapy  offers a promising approach for treating systemic autoimmune diseases characterized by pathognomonic auto-antibodies, primarily due to B cell dysregulation. Early findings indicate that a single infusion of CD19-CAR-T cells is not only safe but also capable of inducing enduring remission without the need for ongoing medication in patients with conditions such as systemic lupus erythematosus (SLE) and other autoimmune disorders. However, further controlled clinical studies are necessary to establish both the safety and efficacy of CD19-CAR-T cell therapy in treating autoimmune diseases.

During the EHA 2024 conference, part I of the CASTLE study (NCT06347718) is presented. CASTLE study is sponsored by University of Erlangen-Nürnberg Medical School and contains two phase, Phase I: Evaluating the safety of CAR-T-Cells in systemic autoimmune diseases with 8 patients and Phase II: Evaluating the efficiency of CAR-T-Cells in systemic autoimmune diseases with 16 patients. Autologous CD19 CAR T cells MB-CART19.1 were produced with the Miltenyi prodigy platform.

The phase I of the CASTLE study involved 8 participants, with treatments administered to 5 individuals for SLE, 2 for Systemic sclerosis (SSc), and 1 for Idiopathic inflammatory myositis (IIM). 

Among the participants, 6 were female and 2 were male. The median age was 33.5 years, ranging from 20 to 81 years. Disease duration ranged from 1 to 9 years, with a median of 3 years. The follow-up months range from 6 to 9 months.

From all 8 patients, safety data and B cell/CAR-T cell efficacy data were available, while clinical efficacy data were available from 5/8 patients with sufficiently long follow-up (≥6 weeks). 

No higher grade cytokine release syndrome (CRS) (grade 3 or 4) was observed (grade 0: N=3; grade 1: N=4; grade 2: N=1). No immune effector cell-associated neurotoxicity syndrome (ICANS) and no prolonged bone marrow toxicity (grade III/IV neutropenia/leucocytopenia >28 days) were observed. Adverse event of special interest (AESI) were two late-stage neutropenias that resolved with G-CSF treatment, one flare of SLE before CAR-T cell therapy that required glucocorticoids and two cases of pneumonia (SARSCoV-2 and CMV) that resolved upon treatment. B cells were completely depleted in all patients within 10 days.

CAR T cells expand and peak on day 10 and they disappear before 6 months. B cell were abrogated by day 7 and B cells replenish between 60 and 120 days (1 not recovered yet), one predefined DLT was observed (Kidney function worsened to grade 3 for more than 7 days).

KOL insights

"To further advance this field, additional experiments should be conducted with larger sample sizes, longer experimental timelines, and rigorous long-term safety monitoring. By building upon the knowledge gained from CAR-T treatment for hematological tumors, there is an opportunity to optimize the clinical application of CAR-related therapy for R/R autoimmune diseases," -Prof United States.

Conclusion 

CAR-T cell therapy is a highly individualized and specialized treatment. Currently, the US FDA has approved six CAR T-cell therapies: ABECMA (idecabtagene vicleucel), BREYANZI (lisocabtagene maraleucel), KYMRIAH (tisagenlecleucel), CARVYKTI (ciltacabtagene autoleucel), TECARTUS (brexucabtagene autoleucel), YESCARTA (axicabtagene ciloleucel). The CAR-T cell has been used predominantly in the treatment of hematological malignancies, including large B-cell lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma.

Researchers are investigating CAR-T’s possible use in autoimmune illnesses as a result of its ability to eradicate pathogenic B cells and produce long-lasting remissions. Data from the CASTLE study showed that the primary endpoint and secondary endpoint  both are met during the study.

For autoimmune illnesses that have relapsed or are resistant, CAR-T cell treatment has demonstrated significant efficacy and safety. However, the field of CAR-cell therapy for autoimmune illnesses is still somewhat in early stages, even with these encouraging developments. To determine how successful the treatment will be over time, extended follow-up is necessary. In addition to this, maximizing the practical use of CAR-related therapy for relapse/ Refractory autoimmune illnesses is possible by expanding on the information obtained from CAR-T treatment for hematological cancers.