Preclinical Evaluation of B7-H3-specific Chimeric Antigen Receptor T Cells for the Treatment of Acute Myeloid Leukemia.

Autor:	Lichtman EI; Division of Hematology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina. eben_lichtman@med.unc.edu.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina., Du H; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina., Shou P; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina., Song F; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina., Suzuki K; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina., Ahn S; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina., Li G; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina., Ferrone S; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Su L; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina., Savoldo B; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina., Dotti G; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Jun 01; Vol. 27 (11), pp. 3141-3153. Date of Electronic Publication: 2021 Feb 02.
DOI:	10.1158/1078-0432.CCR-20-2540
Abstrakt:	Purpose: The development of safe and effective chimeric antigen receptor (CAR) T-cell therapy for acute myeloid leukemia (AML) has largely been limited by the concomitant expression of most AML-associated surface antigens on normal myeloid progenitors and by the potential prolonged disruption of normal hematopoiesis by the immunotargeting of these antigens. The purpose of this study was to evaluate B7-homolog 3 (B7-H3) as a potential target for AML-directed CAR T-cell therapy. B7-H3, a coreceptor belonging to the B7 family of immune checkpoint molecules, is overexpressed on the leukemic blasts of a significant subset of patients with AML and may overcome these limitations as a potential target antigen for AML-directed CAR-T therapy. Experimental Design: B7-H3 expression was evaluated on AML cell lines, primary AML blasts, and normal bone marrow progenitor populations. The antileukemia efficacy of B7-H3-specific CAR-T cells (B7-H3.CAR-T) was evaluated using in vitro coculture models and xenograft models of disseminated AML, including patient-derived xenograft models. The potential hematopoietic toxicity of B7-H3.CAR-Ts was evaluated in vitro using colony formation assays and in vivo in a humanized mouse model. Results: B7-H3 is expressed on monocytic AML cell lines and on primary AML blasts from patients with monocytic AML, but is not significantly expressed on normal bone marrow progenitor populations. B7-H3.CAR-Ts exhibit efficient antigen-dependent cytotoxicity in vitro and in xenograft models of AML, and are unlikely to cause unacceptable hematopoietic toxicity. Conclusions: B7-H3 is a promising target for AML-directed CAR-T therapy. B7-H3.CAR-Ts control AML and have a favorable safety profile in preclinical models. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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