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Immunotherapy

Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells

Leukemia volume 30, pages 701–707 (2016)Cite this article

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Abstract

Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.

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Authors and Affiliations

  1. R and D, iCell Gene Therapeutics LLC, Long Island High Technology Incubator, Stony Brook, NY, USA

    K Pinz, G W Zieve, A E Firor, X Jiang & Y Ma

  2. Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA

    H Liu, M Golightly, A Jares & Y Ma

  3. Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY, USA

    F Lan, N Hagag & M Schuster

  4. The Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China

    Y Ma

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Correspondence to X Jiang or Y Ma.

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Yupo Ma is a founder and Chairman of iCell Gene Therapeutics, LLC. The other authors declare no conflict of interest.

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Pinz, K., Liu, H., Golightly, M. et al. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. Leukemia 30, 701–707 (2016). https://doi.org/10.1038/leu.2015.311

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