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Versatile strategy for controlling the specificity and activity of engineered T cells

Academic Article
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Overview

authors

  • Ma, J. S. Y.
  • Kim, J. Y.
  • Kazane, Stephanie Ann
  • Choi, S. H.
  • Yun, H. Y.
  • Kim, M. S.
  • Rodgers, D. T.
  • Pugh, H. M.
  • Singer, O.
  • Sun, Sophie Biyu
  • Fonslow, B. R.
  • Kochenderfer, J. N.
  • Wright, T. M.
  • Schultz, Peter
  • Young, Travis Scott
  • Kim, C. H.
  • Cao, Y.

publication date

  • January 2016

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general application of current CAR-T--cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as "switch" molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a "universal" anti-FITC-directed CAR-T cell. Optimization of this CAR-switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR-T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy.

subject areas

  • Animals
  • Antigens, CD19
  • Antigens, Neoplasm
  • Azides
  • B-Lymphocytes
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Female
  • Fluorescein-5-isothiocyanate
  • Genetic Vectors
  • Humans
  • Immunotherapy, Adoptive
  • Lentivirus
  • Leukemia, B-Cell
  • Lymphocyte Activation
  • Lymphopenia
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Models, Molecular
  • Phenylalanine
  • Protein Conformation
  • Protein Engineering
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Sialic Acid Binding Ig-like Lectin 2
  • Single-Chain Antibodies
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocytes
  • Transduction, Genetic
  • Xenograft Model Antitumor Assays
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Research

keywords

  • B-cell aplasia
  • cancer immunotherapy
  • chimeric antigen receptor T cell
  • cytokine release syndrome
  • noncanonical amino acids
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Identity

PubMed Central ID

  • PMC4743826

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1524193113

PubMed ID

  • 26759368
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Additional Document Info

start page

  • E450

end page

  • E458

volume

  • 113

issue

  • 4

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