Journal
NATURE BIOTECHNOLOGY
Volume 38, Issue 4, Pages 420-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41587-019-0404-8
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Funding
- NIH [R41-CA213678]
- Proton Beam/Federal Share Program
- MGH ECOR
- NCI [R35-CA197743, U01-CA 224348, P01-CA080124, R01-CA208205]
- Ludwig Center at Harvard
- National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health in the Department of Health and Human Services [HHSN272201300006C]
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Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody-peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8(+) T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies. Anti-tumor activity of cytomegalovirus (CMV)-specific CD8 T cells is achieved by antibody-mediated delivery of CMV epitopes.
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