Redirecting αβT cells against cancer cells by transfer of a broadly tumor-reactive γδT-cell receptor

Major limitations of currently investigated alpha beta T cells redirected against cancer by transfer of tumor-specific alpha beta TCR arise from their low affinity, MHC restriction, and risk to mediate self-reactivity after pairing with endogenous alpha or beta TCR chains. Therefore, the ability of a defined gamma 9 delta 2TCR to redirect alpha beta T cells selectively against tumor cells was tested and its molecular interaction with a variety of targets investigated. Functional analysis revealed that a gamma 9 delta 2TCR efficiently reprograms both CD4(+) and CD8(+) alpha beta T cells against a broad panel of cancer cells while ignoring normal cells, and substantially reduces but does not completely abrogate alloreactivity. gamma 9 delta 2TCR-transduced alpha beta T cells reduced colony formation of progenitor cells of primary acute myeloid leukemia blasts and inhibited leukemia growth in a humanized mouse model. Thereby, metabolites of a dysregulated mevalonate pathway are targeted and the additional application of widely used biphosphonates is crucial for in vivo efficacy most likely because of its modulating effect on cytokine secretion of gamma 9 delta 2TCR-transduced alpha beta T cells. Expression of NKG2D ligands and F1-ATPase contributed to the activity of gamma 9 delta 2TCR-transduced alpha beta T cells but were not mandatory. In summary, gamma 9 delta 2TCRs are an attractive alternative to broadly redirect alpha beta T cells against cancer cells with both an improved efficacy and safety profile compared with currently used alpha beta TCRs. (Blood. 2011;118(1):50-59)