Improved anti-leukemia activities of adoptively transferred T cells expressing bispecific T-cell engager in mice.
Despite the impressive clinical efficacy of T cells engineered to express chimeric antigen receptors (CAR-Ts), the current applications of CAR-T cell therapy are limited by major treatment-related toxicity. Thus, safer yet effective alternative approaches must be developed. In this study, we compared CD19 bispecific T-cell engager (BiTE)-transferred T cells that had been transfected by RNA electroporation with CD19 CAR RNA-transferred T cells both in vitro and in an aggressive Nalm6 leukemia mouse model. BiTEs were secreted from the transferred T cells and enabled both the transferred and bystander T cells to specifically recognize CD19(+) cell lines, with increased tumor killing ability, prolonged functional persistence, increased cytokine production and potent proliferation compared with the CAR-T cells. More interestingly, in comparison with CD3/CD28 bead-stimulated T cells, T cells that were expanded by a rapid T-cell expansion protocol (REP) showed enhanced anti-tumor activities for both CAR and BiTE RNA-electroporated T cells both in vitro and in a Nalm6 mouse model (P<0.01). Furthermore, the REP T cells with BiTE RNAs showed greater efficacy in the Nalm6 leukemia model compared with REP T cells with CAR RNA (P<0.05) and resulted in complete leukemia remission.
Center for Cellular Immunotherapies, University of Pennsylvania Cancer Center, Philadelphia, PA, USA.
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X
Liu
Division of Oncology, Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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DM
Barrett
Center for Cellular Immunotherapies, University of Pennsylvania Cancer Center, Philadelphia, PA, USA.
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S
Jiang
Center for Cellular Immunotherapies, University of Pennsylvania Cancer Center, Philadelphia, PA, USA.
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C
Fang
Center for Cellular Immunotherapies, University of Pennsylvania Cancer Center, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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M
Kalos
Division of Oncology, Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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SA
Grupp
Center for Cellular Immunotherapies, University of Pennsylvania Cancer Center, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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June
Center for Cellular Immunotherapies, University of Pennsylvania Cancer Center, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Y
Zhao
D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy; D006801:Humans; D016219:Immunotherapy, Adoptive; D007938:Leukemia / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D018941:Antigens, CD19; D015514:Oncogene Proteins, Fusion; D011946:Receptors, Antigen