CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia. Academic Article uri icon

Overview

abstract

  • Although many adults with B cell acute lymphoblastic leukemia (B-ALL) are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs) and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3ΞΆ/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL.

publication date

  • April 9, 2013

Research

keywords

  • Antigens, CD19
  • B-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Immunotherapy, Adoptive
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Receptors, Antigen, T-Cell

Identity

PubMed Central ID

  • PMC3621858

Scopus Document Identifier

  • 84876050411

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0061338

PubMed ID

  • 23585892

Additional Document Info

volume

  • 8

issue

  • 4