Genetic modification of T cells with IL-21 enhances antigen presentation and generation of central memory tumor-specific cytotoxic T-lymphocytes

An optimized antigen-presenting cell for tumor immunotherapy should produce a robust antigen specific cytotoxic T lymphocytes (CTL) response to tumor-associated antigens, which can persist in vivo and expand on antigen reencounter. Interleukin (IL)-21 synergizes with other γ-chain cytokines to enhance the frequency and cytotoxicity of antigen-specific CTL. As T cells themselves may serve as effective antigen-presenting cells (T antigen-presenting cells; TAPC) and may be useful in vivo as cellular vaccines, we examined whether CD8 T cells genetically modified to produce IL-21 could induce immune responses to tumor associated antigen peptides in healthy human leukocyte antigen-A2 donors. We found that IL-21 modified TAPC enhanced both the proliferation and survival of MART-1 specific CD8 T cells, which were enriched by >8-fold over cultures with control nontransgenic TAPC. MART-1-specific CTL produced interferon-γ in response to cognate peptide antigen and killed primary tumor cells expressing MART-1 in a major histocompatibility complex restricted manner. IL-21 modified TAPC similarly enhanced generation of functional CTL against melanoma antigen gp100 and the B-cell chronic lymphocytic leukemia associated RHAMM antigen. Antigen-specific CTL generated using IL-21 gene-modified TAPC had a central memory phenotype characterized by CD45RA, CD44, CD27, CD28, CD62L, and IL-7 receptor-α, contrasting with the terminal effector phenotype of CTL generated in the absence of IL-21. Thus, TAPC stimulation in the presences of IL-21 enhances proliferation of tumor antigen-specific T cells and favors induction of a central memory phenotype, which may improve proliferation, survival, and efficacy of T-cell based therapies for the treatment of cancer.