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Adoptively Transferred Tumor-Specific T Cells Stimulated Ex vivo Using Herpes Simplex Virus Amplicons Encoding 4-1BBL Persist in the Host and Show Antitumor Activity In vivo

¹ Department of Microbiology and Immunology and ² Biostatistics Department, University of Miami Miller School of Medicine, and ³ University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida; ⁴ Department of Oncology, Hebrew University Hadassah School of Medicine, Jerusalem, Israel; ⁵ Department of Neurology and ⁶ Center for Aging and Developmental Biology, University of Rochester School of Medicine, Rochester, New York; and ⁷ Georgetown University Medical Center, Washington, District of Columbia

Requests for reprints: Joseph D. Rosenblatt, Division of Hematology/Oncology, University of Miami Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue (D8-4), Suite 3300, Miami, FL 33136. Phone: 305-243-9528; Fax: 305-243-9161; E-mail: jrosenblatt{at}med.miami.edu.

4-1BB is a T-cell costimulatory receptor which binds its ligand 4-1BBL, resulting in prolonged T cell survival. We studied the antitumor effects of adoptively transferred tumor-specific T cells expanded ex vivo using tumors transduced with herpes simplex virus (HSV) amplicons expressing 4-1BBL as a direct source of antigen and costimulation. We constructed HSV amplicons encoding either the 4-1BBL (HSV.4-1BBL) or B7.1 (HSV.B7.1) costimulatory ligands. Lewis lung carcinoma cells expressing ovalbumin (LLC/OVA) were transduced with HSV.4-1BBL, HSV.B7.1, or control HSV amplicons and used to stimulate GFP⁺ OVA-specific CD8⁺ T cells (OT-1/GFP) ex vivo. Naive or ex vivo stimulated OT-1/GFP cells were adoptively transferred into LLC/OVA tumor-bearing mice. Higher percentages of OT-1/GFP cells were seen in the peripheral blood, spleen, and tumor bed of the HSV.4-1BBL–stimulated OT-1/GFP group compared with all other experimental groups. OT-1 cells identified within the tumor bed and draining lymph nodes of the HSV.4-1BBL–stimulated OT-1 group showed enhanced bromodeoxyuridine (BrdUrd) incorporation, suggesting ongoing expansion in vivo. Mice receiving HSV.4-1BBL–stimulated OT-1/GFP had significantly decreased tumor volumes compared with untreated mice (P < 0.001) or to mice receiving naive OT-1/GFP (P < 0.001). Transfer of HSV.B7.1-stimulated OT-1/GFP did not protect mice from tumor. Mice that received HSV.4-1BBL–stimulated OT-1/GFP exhibited increased cytolytic activity against LLC/OVA and higher percentages of Ly-6C⁺ OT-1/GFP in the spleen and tumor bed compared with controls. Tumor-specific T cells stimulated ex vivo using tumor transduced with HSV.4-1BBL expand in vivo following adoptive transfer, resulting in tumor eradication and the generation of tumor-specific CD44⁺Ly-6C⁺CD62L^– effector memory T cells. [Cancer Res 2007;67(20):10027–37]

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