CD19.CAR T Cells(University Hospital Heidelberg)

Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) typically experience dismal outcomes. Although CD19 chimeric antigen receptor-T (CAR-T) cell therapy has shown considerable efficacy, the factors influencing its long-term efficacy remain unclear. This study was designed to identify common factors influencing long-term therapeutic efficacy and clinical prognosis, and furthermore to systematically characterize the long-term safety profile. We retrospectively analyzed 79 R/R B-NHL patients treated with CD19 CAR-T cell therapy at our center to evaluate efficacy, long-term survival, and prognostic factors. Among all evaluable patients, the overall response rate was 89.7%, with a 3-year duration of response (DOR) of 44.9% (95% CI, 34.2%-59.0%), a 3-year progression-free survival (PFS) of 40.2% (95% CI, 30.3%-53.4%), and a 3-year overall survival (OS) of 48.3% (95% CI, 38.0%-61.3%). Long-term adverse events (AEs) included hypogammaglobulinemia, which occurred in 73 of 74 evaluable patients (92.4%), viral reactivation (5.1%), and secondary malignancy (5.1%). Notably, high tumor Ki-67 (>60%) was associated with lower peak CAR-T cell expansion (P < .01), reduced area under the curve of expansion from day 0 to 28 (P < .0001), and inferior complete response rate, DOR, and PFS (all P < .05). However, CAR-T cell persistence was not significantly associated with long-term remission or survival (all P > .05). CD19 CAR‑T cell therapy yielded sustained remissions in patients with R/R B-NHL, with manageable long-term AEs. High tumor Ki‑67 expression serves as a poor prognostic factor and is linked to limited CAR‑T cell expansion, whereas CAR‑T cell persistence does not influence long-term prognosis.

The role of autoantibody-producing B cells in connective tissue diseases (CTD) has recently been highlighted by the successful treatment with CD19-targeting CAR T cells. Detrimental effects of autoantibodies are linked to the formation of deposited IgG complexes and the activation of immune cells via Fcγ receptors (FcγRs). The role of circulating immune complexes (cICs) as a link between adaptive and innate immunity has remained understudied. Clinical testing of cICs has been hindered by the lack of reliable detection methods. The aim of this study was to determine the potential of IgG-containing cICs to activate FcγRs (their bioactivity) using a new detection method.

A reporter cell platform was used to assess the presence and bioactivity of cICs in IgG-autoantibody-positive CTD patients (cross-section analysis) and in patients treated with CD19-CAR T cells (longitudinal analysis).

The bioactivity of cICs in the cohort of patients with CTDs was significantly higher compared with healthy controls and patients with IgG-autoantibody-negative systemic inflammatory disease (psoriatic arthritis). Analyses of individual diseases revealed the presence of cICs in the sera of all CTDs, including systemic sclerosis (SSc) and primary Sjögren’s syndrome, although there was significant heterogeneity among individuals. Within SSc, patients positive for anti-topoisomerase-I (Scl70) autoantibodies, diffuse cutaneous and lung involvement had significantly enhanced cIC bioactivity. Finally, the bioactivity of cICs was significantly reduced in CTD patients after CD19-CAR T cell therapy.

Our study reveals the presence of FcγR-engaging cICs in CTDs and demonstrates that the bioactivity of cICs is correlated with clinical phenotypes and treatment outcomes.