Engineered off-the-shelf therapeutic T cells resist host immune rejection.
Nat Biotechnol
; 39(1): 56-63, 2021 01.
Article
in En
| MEDLINE
| ID: mdl-32661440
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Antigen, T-Cell
/
T-Lymphocytes
/
Cell Engineering
/
Receptors, Chimeric Antigen
/
Graft Rejection
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Biotechnol
Journal subject:
BIOTECNOLOGIA
Year:
2021
Type:
Article
Affiliation country:
United States