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

Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE

Publication: 2000- : London : Nature Publishing Group, Specialist Journals
Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987-

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

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.

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P30 CA021765 United States CA NCI NIH HHS; CA21765 United States CA NCI NIH HHS

0 (Antigens, CD19)
0 (KMT2A protein, human)
0 (Receptors, Antigen)
149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
EC 3.1.3.48 (Leukocyte Common Antigens)

Date Created: 20140604 Date Completed: 20150406 Latest Revision: 20240511

20240511

PMC4275423

10.1038/leu.2014.174

24888271