Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells

Abstract

CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse eventsdefined as starting or persisting beyond 90 days after CART cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG <400 mg/dL or i.v immunoglobulinm (IVIG) replacement, observed in 67% of the patients with available data. Infection density was .55 infection/100 days at risk (2.08 per patient-year). The majority (80%) of the infections were treated in the outpatient setting, and 5% necessitated admission to the intensive care unit (ICU). Subsequent malignancies occurred in 15% of patients, including 5% with myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenia requiring transfusions or growth factor support. Graft-versus-host disease occurred in 3 of 15 patients (20%) who had undergone previous allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe, and many could be related to previous or subsequent therapies, suggesting a safe longterm profile of CD19-targeted CART cell immunotherapy.

Emerging Approaches for Regulation and Control of CAR T Cells: A Mini Review

“…The recent years' success of CAR T cells in the clinic has revealed the serious and potentially lethal side effects associated with the potent treatment, including off-tumor, on-target effects, systemic inflammatory conditions such as CRS and acute neurotoxicity (90,91). More recently it has become clear that cardiovascular and gastrointestinal events can also occur post-CAR-T (92,93).…”

Infections following CAR-T cells therapy: current state-of-the-art review and recommendations

“…Up to the end of 2019, only a few studies dedicated to infections after CAR-T cells therapy have been published [8][9][10][11][12]. All major studies on CAR-T cells therapy report adverse events including infectious complications.…”

Late Events After CD-19 CAR-T Treatment

“…However, as experience with CD19-directed T cell therapy has grown, there is an increased awareness of the long-term adverse events. The article by Cordeiro et al [5] fills an important gap in the literature by reporting on long-term adverse events in a cohort of patients with a variety of B cell malignancies (ALL, non-Hodgkin lymphoma, or chronic lymphocytic leukemia) treated with CD19 CAR T cells in a single-site phase I/II study (NCT01865617). The authors limited their analysis to a cohort of patients who survived at least a year after receiving CAR T cell therapy and excluded all patients who had subsequent lines of therapy, including allogeneic stem cell transplant.…”

“…There is clear evidence that the choice of CAR construct costimulatory cassette impacts the persistence and function of CAR T cells [10][11][12]. CD19 CAR T cell persistence is the likely culprit for many of the late-term adverse events reported by Cordeiro et al [5], especially the persistent HGG as well as the late onset of infections, immune-related events, and neurologic/ psychiatric events. One solution to long-term T cell persistence would be including a suicide gene into the vector [13][14][15][16][17].…”

“…Universal CAR T cells themselves persist long term but only function after they are loaded with a receptor/antibody in vivo. This single-site report by Cordeiro et al [5] raises concerns about critical late adverse events in CD19 CAR T cell patients, but solutions are on the horizon. Further investigation using a larger patient cohort and other clinical grade CD19 CAR construct use by other investigators is required to improve the safety of CD19 CAR T cell therapy.…”