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Immunosuppressant therapy averts rejection of allogeneic FKBP1A-disrupted CAR-T cells.
Mol Ther
October 2024
Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA 02139, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02115, USA.
Chimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of allogeneic CAR-T cells may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin and tacrolimus effectively mitigate allorejection of HLA-mismatched CAR-T cells in immunocompetent humanized mice, extending their in vivo persistence to that of syngeneic humanized mouse-derived CAR-T cells.
View Article and Find Full Text PDFHumanization of the antigen-recognition domain does not impinge on the antigen-binding, cytokine secretion, and antitumor reactivity of humanized nanobody-based CD19-redirected CAR-T cells.
J Transl Med
July 2024
Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Background: The immunogenicity of the antigen-recognition domains of chimeric antigen receptor (CAR)-T cells leads to immune responses that may compromise the antitumor effects of the adoptively transferred T cells. Herein, we attempt to humanize a CD19-specific VHH (named H85) using in silico techniques and investigate the impact of antigen-recognition domain humanization on CAR expression and density, cytokine secretion, and cytolytic reactivity of CAR-T cells based on the humanized VHH.
Methods: H85 was humanized (named HuH85), and then HuH85 was compared with H85 in terms of conformational structure, physicochemical properties, antigenicity and immunogenicity, solubility, flexibility, stability, and CD19-binding capacity using in silico techniques.
[Long-term safety and activity of humanized CD19 chimeric antigen receptor T cells for children and young adults with relapsed/refractory acute lymphoblastic leukemia].
Zhonghua Xue Ye Xue Za Zhi
July 2022
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
To investigate the efficacy and safety of humanized CD19-specific chimeric antigen receptor T cells (hCART19s) in treating children and young adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) and to analyze relevant factors affecting its curative effect and prognosis. We conducted a single-center clinical trial involving 31 children and young adult patients with R/R B-ALL who were treated with humanized CD19-specific CAR-T cells (hCART19s) from May 2016 to September 2021. Results showed that 27 (87.
View Article and Find Full Text PDFSafety and efficacy of a humanized CD19 chimeric antigen receptor T cells for relapsed/refractory acute lymphoblastic leukemia.
Am J Hematol
June 2022
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
CD19-targeted chimeric antigen receptor T (CAR-T) cells using murine single-chain variable fragment (scFv) has shown substantial clinical efficacy in treating relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, potential immunogenicity of the murine scFv domain may limit the persistence of CAR-T cells. In this study, we treated 52 consecutive subjects with R/R ALL with humanized CD19-specific CAR-T cells (hCART19s).
View Article and Find Full Text PDFOvercoming leukemia heterogeneity by combining T cell engaging bispecific antibodies.
J Immunother Cancer
November 2020
Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Background: Leukemia represents about 5% of all human cancers. Despite advances in therapeutics, a substantial number of patients succumb to the disease. Several subtypes of leukemia are inherently more resistant to treatment despite intensive chemotherapy or targeted therapy.
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