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

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.

journal_name

Nat Biotechnol

journal_title

Nature biotechnology

authors

Mo F,Watanabe N,McKenna MK,Hicks MJ,Srinivasan M,Gomes-Silva D,Atilla E,Smith T,Ataca Atilla P,Ma R,Quach D,Heslop HE,Brenner MK,Mamonkin M

doi

10.1038/s41587-020-0601-5

subject

Has Abstract

pub_date

2021-01-01 00:00:00

pages

56-63

issue

1

eissn

1087-0156

issn

1546-1696

pii

10.1038/s41587-020-0601-5

journal_volume

39

pub_type

杂志文章

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