Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity
| Autor: | Yimei Li, John T. Gray, C H Pui, Paul Eldridge, Duangchan Suwannasaen, Wing Keung Chan, Wing Leung, Robert E. Throm, Jim Houston |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Adoptive cell transfer T-Lymphocytes Antigens CD19 Drug Resistance Graft vs Host Disease chemical and pharmacologic phenomena Biology Cell therapy Mice Antigen NK-92 immune system diseases Recurrence hemic and lymphatic diseases Cell Line Tumor Neoplasms medicine Animals Humans Leukemia hemic and immune systems Hematology Histone-Lysine N-Methyltransferase medicine.disease Flow Cytometry Haematopoiesis Receptors Antigen Oncology Drug Resistance Neoplasm Immunology Leukocytes Mononuclear Myeloid-Lymphoid Leukemia Protein Leukocyte Common Antigens Original Article Stem cell Immunologic Memory Signal Transduction |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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