Abstract
BackgroundCellular immunotherapies, such as chimeric antigen receptor modified-T cell (CAR-T) therapy, offers excellent potential for tumor treatment. The memory phenotype of CAR-T has been correlated positively with a therapeutic effect on and prognosis of cancer.MethodThe proliferation rates of novel CAR-T was determined by cell counting. The phenotypes of CAR-T cells were then detected by flow cytometry. The cell cytotoxicity against tumor cells in vitro was investigated by lactate dehydrogenase assay and luciferase assay. The cytokines secreted during these assays were determined by the cytometric bead array assay. The antitumor ability in vivo was evaluated in NOG mice.ResultsCo-expression of an LRP6 full-length protein with anti-CD19 CAR significantly improved the memory phenotype of CAR-positive T-cells by enhancing the wnt signaling pathway. As compared with anti-CD19 CAR-T, anti-CD19 CAR-T-LRP6 exhibited more robust cytotoxicity against tumor cells in vitro and in vivo, albeit fewer cytokines were released in vitro. Moreover, the longer survival rate and robust expansion in vivo of anti-CD19 CAR-T-LRP6 cells were found to be effective in inhibiting cancer recurrence.ConclusionsCAR co-expressed with LRP6 could sustain the memory phenotype that enabled permanent relief and may further assist in the development of potent and durable T-cell therapeutics.
Highlights
Chimeric antigen receptor-engineered T (CAR-T) cell therapy was suggested as one of the most promising approaches for tumor treatment, especially for leukemia and lymphoma [1]
CD19 BBZ-LRP6 for B-ALL Treatment tisagenlecleucel [3,4,5] for adult B-cell acute lymphoblastic leukemia (B-ALL) and the axicabtagene ciloleucel for large B-cell non-Hodgkin lymphoma [6, 7]
To confirm whether LRP6 was expressed on the surface of α19BBZ-LRP6, the α19BBZLRP6 and α19BBZ T cells were examined using CD19 protein (CD19-PE) protein and anti-LRP6 antibody, followed by labeling with antigen-presenting cells (APC)-linked anti-rabbit IgG APC antibody
Summary
Chimeric antigen receptor-engineered T (CAR-T) cell therapy was suggested as one of the most promising approaches for tumor treatment, especially for leukemia and lymphoma [1]. Two FDA-approved CAR-T-cell therapies targeting the CD19 molecule are available: the Abbreviations: APC, antigen-presenting cell; B-ALL, B-cell acute lymphoblastic leukemia; CAR-T: chimeric antigen receptor modified T cell. Several clinical studies have demonstrated that the clinical response to anti-CD19 CAR-T is positively correlated with an increasing population of the central memory T cells [13]. Cellular immunotherapies, such as chimeric antigen receptor modifiedT cell (CAR-T) therapy, offers excellent potential for tumor treatment. The memory phenotype of CAR-T has been correlated positively with a therapeutic effect on and prognosis of cancer
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