CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

Nat Med. 2021 Oct;27(10):1797-1805. doi: 10.1038/s41591-021-01497-1. Epub 2021 Oct 12.

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antigens, CD19 / genetics*
  • Antigens, CD19 / immunology
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Immunotherapy / adverse effects
  • Immunotherapy / trends
  • Immunotherapy, Adoptive / adverse effects
  • Immunotherapy, Adoptive / trends
  • Infant
  • Male
  • Pediatrics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / therapy*
  • Progression-Free Survival
  • Receptors, Chimeric Antigen / administration & dosage*
  • Receptors, Chimeric Antigen / immunology
  • Sialic Acid Binding Ig-like Lectin 2 / genetics*
  • Sialic Acid Binding Ig-like Lectin 2 / immunology
  • Young Adult

Substances

  • Antigens, CD19
  • Receptors, Chimeric Antigen
  • Sialic Acid Binding Ig-like Lectin 2