Abstract

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.

Highlights

  • Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL)

  • AUTO3 is a dual chimeric antigen receptor (CAR) T cell treatment generated through the transduction of autologous T cells with an RD114 pseudotyped, bicistronic γ-retroviral vector encoding a CD19 and CD22 CAR separated by a self-cleaving 2A peptide, transcribed from a single promoter (Fig. 1a)

  • The CD19-binding moiety was derived from the HD37 antibody and targets a dominant epitope on the protein that is shared with other CD19-binding antibodies including FMC63; the CD22-binding moiety was derived from the LT22 antibody and targets the Ig-like C2-type 5 domain (Extended Data Fig. 1a)

Read more

Summary

Introduction

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. CD19 and CD22 chimeric antigen receptor (CAR) T cell therapies have shown promising efficacy in relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL). Based on the results of the pre-clinical data, we designed a phase 1 clinical study with AUTO3 in pediatric and young adult patients with relapsed or refractory B-lineage ALL (AMELIA trial; NCT03289455, EUDRA CT 2016-004680-39). We report the pre-clinical experiments with AUTO3 together with the safety and efficacy results of this phase 1 clinical trial

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call