Safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell therapy for patients with relapsed/refractory B-ALL

Abstract

Background: Murine chimeric antigen receptor T (CAR-T) cell therapy has demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, the potential immunogenicity of the murine single-chain variable fragment domain may limit the persistence of CAR-T cell, leading to relapse.

Methods: We performed a clinical trial to determine the safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell (hCART19) for R/R B-ALL. Fifty-eight patients (aged 13-74 years) were enrolled and treated between February 2020 and March 2022. The endpoints were complete remission (CR) rate, overall survival (OS), event-free survival (EFS), and safety.

Results: Overall, 93.1% (54/58) of patients achieved CR or CR with incomplete count recovery (CRi) by day 28, with 53 patients having minimal residual disease negativity. With a median follow-up of 13.5 months, the estimated 1-year OS and EFS were 73.6% (95% CI 62.1% to 87.4%) and 46.0% (95% CI 33.7% to 62.8%), with a median OS and EFS of 21.5 months and 9.5 months, respectively. No significant increase in human antimouse antibodies was observed following infusion (p=0.78). Duration of B-cell aplasia in the blood was observed for as long as 616 days, which was longer than that in our prior mCART19 trial. All toxicities were reversible, including severe cytokine release syndrome, which developed in 36% (21/58) of patients and severe neurotoxicity, which developed in 5% (3/58) of patients. Compared with our prior mCART19 trial, patients treated with hCART19 had longer EFS without increased toxicity. Additionally, our data also suggest that patients treated with consolidation therapy, including allogeneic hematopoietic stem cell transplantation or CD22-targeted CAR-T cell, following hCART19 therapy had a longer EFS than those without consolidation therapy.

Conclusion: hCART19 has good short-term efficacy and manageable toxicity in R/R B-ALL patients.

Trial registration number: NCT04532268.

Keywords: Clinical Trials as Topic; Cytotoxicity, Immunologic; Hematologic Neoplasms; Immunity, Cellular; Immunotherapy, Adoptive.

Figure 1

Survival outcomes. Event-free survival (EFS) (A) and overall survival (OS) (B).

Figure 2

Treatment-emergent adverse events. ALT, aminotransferase; CRS, cytokine release syndrome; Cr, creatinine; GVHD, graft-versus-host disease.

Figure 3

Serum cytokines associated with CRS. The peak IFN-γ and IL-6 concentrations (A) and ferritin and CRP levels (B) in serum after infusion in patients with grade 0–2 CRS and grade 3–5 CRS are shown. Each point represents a value from one patient. The peak serum levels of IL-6 (C) and IFN-γ (D) in patients who developed grades 3–5 CRS are compared with those in patients who developed grades 0–2 CRS. CRP, C reactive protein; CRS, cytokine release syndrome.

Figure 4

Prognosis of patients after hCART19 therapy. Event-free survival (EFS) (A) and overall survival (OS) (B) of complete remission (CR) patients in the three groups.

Figure 5

hCART19 expansion and persistence in vivo as assessed via flow cytometry. (A) The postinfusion percentage of CAR+/CD3+cells in peripheral blood in patients with grades 0–2 CRS and grades 3–5 CRS. (B) The postinfusion percentage of CAR+/CD3+cells in peripheral blood in patients who relapsed or did not respond (NR) or had an ongoing response. CAR-T, chimeric antigen receptor T; CRS, cytokine release syndrome; CAR T, chimeric antigen receptor T.

Figure 6

Survival according to CAR T product. Event-free survival (EFS) (A) and overall survival (OS) (B). CAR T, chimeric antigen receptor T.