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Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):740-745. doi: 10.1073/pnas.1614315114. Epub 2017 Jan 9.

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors.

Author information

1
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53213.
2
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226.
3
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226.
4
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
5
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142.
6
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53213; weiguo.cui@bcw.edu.

Abstract

Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors.

KEYWORDS:

CD8 T cells; Listeria; adoptive cell transfer; immunotherapy; melanoma

PMID:
28069963
PMCID:
PMC5278465
DOI:
10.1073/pnas.1614315114
[Indexed for MEDLINE]
Free PMC Article

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