Discussion
MM, Cytopenia, CRS, AQP4-IgG-positive NMOSD, cytopenia, neurological disability, NMOSD
HAND INFECTION, HEMATOLOGICAL MALIGNANCIES, CYTOPENIA, DISEASE, OTHER AUTOIMMUNE DISEASE, AUTOIMMUNE DISEASES, CYTOPENIA, HEMATOLOGIC CANCER, CYTOTOXICITY, INFLAMMATORY RESPONSE
In this ongoing phase 1, first-in-human clinical study of CT103A, CAR T-cell therapy targeting BCMA, in relapsed or refractory AQP4-IgG seropositive NMOSD, patients displayed a manageable safety profile and had a promising clinical response without any additional immunosuppressive therapy.In our recent study, patients with MM were administrated with CT103A at different doses of 1 × 10AEs, mainly presented as cytopenia and infection in our study, occurred in all patients. Cytopenia are common AEs during the first few days after infusion, which might be due to lymphodepletion therapy. Both the severity and duration of cytopenia in our cohort were much lower than those in MM patients,It has been reported that 28% of the CT103A treated MM patients had CRS of grade 3 or higher,CAR T-cell expansion was observed in all 12 dosed patients within 14 days at both doses, and was slightly greater in those patients with a higher dose, a phenomenon similar to other studies of CAR T-cell therapy in hematologic cancer.During the follow-up of a median 5.5 months, we observed reduced attack frequency, and stabilized or improved neurological disability measures in most patients, indicating a preliminary clinical efficacy of CAR-BCMA therapy in NMOSD. The possibility that the lymphodepletion conditioning regimen before CT103A infusion was responsible for an apparent decrease in relapses should also be considered. Lymphodepletion therapy with combination of cyclophosphamide plus fludarabine was wildly used for CAR T-cell expansion and activity in hematological malignancies, which was also adopted in a recent study of CAR T-cell therapy for SLE.Preclinical data indicate that AQP4-IgG triggers amplification of inflammatory response, antibody-dependent and complement-dependent cellular cytotoxicity that can lead to potential injury of astrocytes, surrounding cells, myelin and axons.Moreover, patients with AQP4-IgG-positive NMOSD are often complicated with other autoimmune diseases, such as SS, and RA.This study has several limitations. First, newly approved therapies including eculizumab, satralizumab and inebilizumab were not available or approved for treating NMOSD in China at the time of the initiation of the trial. None of the included patients were ever treated with this medication. A parallel treatment arm with these approved therapies will be set in the future exploration. Second, the follow-up duration is brief, significantly limiting the interpretation of the clinical outcomes. Longer evaluation is continued. Further, the non-randomized design and the small patient number in this trial restrict the conclusions drawn. Lastly, CAR T cells specific for the B cells producing anti-AQP4 antibody or directly targeting the AQP4-IgG would be more accurate for the disease control, which warrant further investigation.This first-in-human study has provided an initial proof-of-concept that CAR-BCMA T cells, CT103A, could serve as a safe and potential monotherapy for patients with relapsed or refractory AQP4-IgG seropositive NMOSD, and warrant further evaluation in wider applications, especially for antibody-mediated autoimmune diseases.