Inaticabtagene Autoleucel

In patients with autoimmune hemolytic anemia (AIHA), the risk of relapse is high owing to persistent autoreactive B-cell activity. Multirefractory AIHA is a more advanced stage of disease that is defined by a lack of response to at least three lines of therapy. CD19-directed chimeric antigen receptor (CAR) T-cell therapy results in profound B-cell depletion and may be a useful approach to achieving drug-free remission in multirefractory AIHA.

We enrolled patients from a compassionate-use program and those from a phase 1 study who had primary multirefractory AIHA. Each patient received a single infusion of autologous CD19 CAR T cells. The primary objective was to assess the safety profile - the incidence, characteristics, and severity of adverse events, including cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome. Secondary objectives included efficacy and pharmacokinetic features. A complete response was defined by resolution of symptoms, an increased hemoglobin level, and normalization of hemolysis markers. B-cell reconstitution and the origin of relapse were analyzed with flow cytometry, single-cell RNA sequencing, and paired B-cell receptor sequencing.

CD19 CAR T cells were administered to 11 patients - 5 in the compassionate-use program and 6 in the phase 1 study. The median follow-up was 12.2 months (range, 7.3 to 21.9). All patients had a complete response; the median time to a complete response was 45 days (range, 21 to 153). The median duration of drug-free remission was 11.5 months (range, 6.8 to 21.0). Cytokine-release syndrome of grade 1 or 2 in severity occurred in 9 patients, and immune effector cell-associated neurotoxicity syndrome of grade 1 occurred in 1 patient. A total of 15 infections occurred among 7 patients, with no infections of grade 4 or higher. One patient had immune effector cell-associated hematotoxicity of grade 3. In multi-omics assessments of sequential samples, naive B cells were predominant in the reconstituted B-cell population in patients with drug-free remission, and crosstalk between HLA-DRB5+ B cells, CD4+ T cells, and B-cell maturation antigen-expressing long-lived plasma cells contributed to a relapse-specific B-cell niche.

CD19 CAR T-cell therapy had expected toxic effects and resulted in sustained remission in patients with multirefractory AIHA. (Funded by the National Key Research and Development Program of China and others; ClinicalTrials.gov number, NCT06231368.).

Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.