Engineered off-the-shelf therapeutic T cells resist host immune rejection

Feiyan Mo, Norihiro Watanabe, Mary K. McKenna, M. John Hicks, Madhuwanti Srinivasan, Diogo Gomes-Silva, Erden Atilla, Tyler Smith, Pinar Ataca Atilla, Royce Ma, David Quach, Helen E. Heslop, Malcolm K. Brenner, Maksim Mamonkin

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Engineered T cells are effective therapies against a range of malignancies, but current approaches rely on autologous T cells, which are difficult and expensive to manufacture. Efforts to develop potent allogeneic T cells that are not rejected by the recipient’s immune system require abrogating both T- and natural killer (NK)-cell responses, which eliminate foreign cells through various mechanisms. In the present study, we engineered a receptor that mediates deletion of activated host T and NK cells, preventing rejection of allogeneic T cells. Our alloimmune defense receptor (ADR) selectively recognizes 4-1BB, a cell surface receptor temporarily upregulated by activated lymphocytes. ADR-expressing T cells resist cellular rejection by targeting alloreactive lymphocytes in vitro and in vivo, while sparing resting lymphocytes. Cells co-expressing chimeric antigen receptors and ADRs persisted in mice and produced sustained tumor eradication in two mouse models of allogeneic T-cell therapy of hematopoietic and solid cancers. This approach enables generation of rejection-resistant, ‘off-the-shelf’, allogeneic T-cell products to produce long-term therapeutic benefit in immunocompetent recipients.

Original languageEnglish (US)
Pages (from-to)56-63
Number of pages8
JournalNature Biotechnology
Volume39
Issue number1
DOIs
StatePublished - Jan 2021

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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