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Modeling the CD8⁺ T Effector to Memory Transition in Adoptive T-Cell Antitumor Immunotherapy

Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida

Requests for reprints: Thomas Malek, Department of Microbiology and Immunology, University of Miami, 1600 Northwest 10th Avenue, Miami, FL 33101. Phone: 305-243-5627; E-mail: tmalek{at}med.miami.edu.

Key Words: Cellular immunotherapy • Immunology • Animal/transgenic models for tumor immunobiology • Immune responses to cancer

Adoptive T-cell therapy with CD8⁺ CTLs is often characterized by poor persistence of the transferred T cells and limited effector responses. Improved persistence and therapeutic efficacy have been noted when antigen-activated CD8⁺ T cells express properties of memory cells. The current study was undertaken to more precisely characterize the development of memory-like CD8⁺ T cells from short-term CTLs in vitro and upon transfer in vivo, including their antitumor activity. Ovalbumin (OVA)–specific OT-I CTLs acquired phenotypic and functional properties of memory cells 2 to 3 days later either by lowering the concentration of antigen to a level that does not support primary responses and providing a survival signal through transgenic Bcl-2 in vitro or simply by transferring early day 3 CTLs to antigen-free lymphoid-replete mice. In lymphoid-replete mice, established OVA-expressing E.G7 tumor was rejected by short-term CTLs that simultaneously acquired memory-like properties in secondary lymphoid tissues, where tumor antigen level remained low. Collectively, these data indicate that CTLs readily converted to memory-like cells upon lowering antigen to a concentration that selectively supports memory responses and suggest that such conversion predicts successful adoptive immunotherapy. [Cancer Res 2008;68(8):2984–92]