Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity

Leukemia. 2015 Feb;29(2):387-95. doi: 10.1038/leu.2014.174. Epub 2014 Jun 3.


Chimeric antigen receptor (CAR)-redirected cellular therapy is an attractive modality for cancer treatment. We hypothesized that allogeneic CAR-engineered CD45RA-negative T cells can control cancer and infection without the risk of graft-versus-host disease (GVHD). We used CD19(+) MLL-rearranged leukemia as prototype because it is an aggressive and generally drug-resistant malignancy. CD45RA(-) cells that were transduced with anti-CD19 CAR containing 4-1BB and CD3ζ signaling domains effectively lysed MLL-rearranged leukemia cell lines and primary blasts in vitro. In a disseminated leukemia mouse model, CAR(+)CD45RA(-) cells significantly reduced leukemia burdens and prolonged overall survival without GVHD. CAR(+) cells were sustainable in blood, and all the treated mice remained leukemia-free even after they were re-challenged with leukemia cells. Despite the transduction process, CD45RA(-) cells retained recall activity both in vitro and in vivo against human pathogens commonly found in cancer patients. In comparison with CD45RA(+) cells, CD45RA(-) cells showed less allogeneic activity in mixed leukocyte reactions and in mouse models. Thus, the use of CAR(+)CD45RA(-) cells can separate GVHD from graft-versus-malignancy effect and infection control. These cells should also be useful in nontransplant settings and may be administered as off-the-shelf third-party cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / metabolism
  • Cell Line, Tumor
  • Drug Resistance
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Graft vs Host Disease / immunology*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Immunologic Memory
  • Leukemia / blood*
  • Leukemia / immunology
  • Leukemia / metabolism
  • Leukocyte Common Antigens / metabolism*
  • Leukocytes, Mononuclear / cytology
  • Mice
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Neoplasms / metabolism
  • Receptors, Antigen / metabolism
  • Recurrence
  • Signal Transduction
  • T-Lymphocytes / cytology*


  • Antigens, CD19
  • KMT2A protein, human
  • Receptors, Antigen
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Leukocyte Common Antigens