Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-01, Vol.114 (4), p.740-745
• Main Authors: Xin, Gang, Schauder, David M., Jing, Weiqing, Jiang, Aimin, Joshi, Nikhil S., Johnson, Bryon, Cui, Weiguo
• Format: Article
• Language: English
• Subjects: Animals; Bacteria; Biological Sciences; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cells; Immunologic Memory - immunology; Immunotherapy; Immunotherapy, Adoptive - methods; Mice; Mice, Inbred C57BL; Neoplasms - immunology; Neoplasms - therapy; Pathogens; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes, Cytotoxic - immunology; Tumors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1614315114

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.