Antibody-mediated delivery of viral epitopes to tumors harnesses CMV-specific T cells for cancer therapy

David G. Millar, Rakesh R. Ramjiawan, Kosuke Kawaguchi, Nisha Gupta, Jiang Chen, Songfa Zhang, Takashi Nojiri, William W. Ho, Shuichi Aoki, Keehoon Jung, Ivy Chen, Feng Shi, James M. Heather, Kohei Shigeta, Laura T. Morton, Sean Sepulveda, Li Wan, Ricky Joseph, Eleanor Minogue, Ashok KhatriAditya Bardia, Leif W. Ellisen, Ryan B. Corcoran, Aaron N. Hata, Sara I. Pai, Rakesh K. Jain, Dai Fukumura, Dan G. Duda, Mark Cobbold

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)420-425
Number of pages6
JournalNature Biotechnology
Volume38
Issue number4
DOIs
Publication statusPublished - 2020 Apr 1

ASJC Scopus subject areas

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

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