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Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

Academic Article
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Overview

authors

  • Rodgers, D. T.
  • Mazagova, M.
  • Hampton, E. N.
  • Cao, Y.
  • Ramadoss, N. S.
  • Hardy, I. R.
  • Schulman, A.
  • Du, J.
  • Wang, F.
  • Singer, O.
  • Ma, J.
  • Nunez, V.
  • Shen, J.
  • Woods, A. K.
  • Wright, T. M.
  • Schultz, Peter
  • Kim, C. H.
  • Young, Travis Scott

publication date

  • January 2016

journal

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

abstract

  • Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens.

subject areas

  • Animals
  • Antigens, CD19
  • Antigens, Neoplasm
  • Azides
  • B-Lymphocytes
  • Basic-Leucine Zipper Transcription Factors
  • Cell Line, Tumor
  • Cytokines
  • Cytotoxicity, Immunologic
  • Dose-Response Relationship, Immunologic
  • Female
  • Genes, Reporter
  • Genetic Vectors
  • Humans
  • Immunotherapy, Adoptive
  • Leukemia, B-Cell
  • Lymphocyte Activation
  • Lymphopenia
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Phenylalanine
  • Protein Engineering
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae Proteins
  • Sialic Acid Binding Ig-like Lectin 2
  • Single-Chain Antibodies
  • Structure-Activity Relationship
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocyte Subsets
  • Xenograft Model Antitumor Assays
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Research

keywords

  • antibody engineering
  • autologous cell therapy
  • cancer
  • chimeric antigen receptor T cell
  • leukemia
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Identity

PubMed Central ID

  • PMC4743815

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1524155113

PubMed ID

  • 26759369
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Additional Document Info

start page

  • E459

end page

  • E468

volume

  • 113

issue

  • 4

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