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The concept to harness a patient’s immune system against cancer is an emerging strategy. The adoptive transfer of autologous T cells to enforce tumor-cell killing by immune mechanisms has indeed shown promising results in the treatment of various types of cancer, especially malignant melanoma. A major drawback of current clinical applications of adoptive cell transfer (ACT), however, is that they generally require laborious ex vivo expansion and/or genetic engi-neering procedures to generate a potent tumor-reactive CD8+ T-cell phenotype. These interventions bear the risk of inser-tional mutagenesis, e.g. as a result of the inappropriate insertion of T-cell receptor-coding lentiviral vectors within proto-oncogenes, potentially causing T-cell leukemogenesis. Moreover, the therapeu-tic efficacy of ACT appears to be limited by immune evasion mechanisms that are in place in the tumor-bearing host, such as those mediated by the secretion of transforming growth factor β (TGFβ) in the tumor microenvironment and by the accumulation of regulatory T cells, both of which severely dampen the in vivo acti-vation, expansion, and tumor homing of transferred tumor-reactive CD8+ T cells. Another obstacle on the way to broadly applicable ACT therapies is the restricted knowledge of tumor antigens that are Engineering effective T-cell based antitumor immunity thomas Gruber,1 reinhard hinterleitner,1 Christa Pfeifhofer-Obermair,1 Dominik wolf2 and Gottfried Baier1,