Redirecting αß T cells against cancer cells by transfer of a broadly tumor-reactive γδT-cell receptor.

ABSTRACT

Major limitations of currently investigated αßT cells redirected against cancer by transfer of tumor-specific αßTCR arise from their low affinity, MHC restriction, and risk to mediate self-reactivity after pairing with endogenous α or ßTCR chains. Therefore, the ability of a defined γ9δ2TCR to redirect αßT cells selectively against tumor cells was tested and its molecular interaction with a variety of targets investigated. Functional analysis revealed that a γ9δ2TCR efficiently reprograms both CD4(+) and CD8(+) αßT cells against a broad panel of cancer cells while ignoring normal cells, and substantially reduces but does not completely abrogate alloreactivity. γ9δ2TCR-transduced αßT 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 γ9δ2TCR-transduced αßT cells. Expression of NKG2D ligands and F1-ATPase contributed to the activity of γ9δ2TCR-transduced αßT cells but were not mandatory. In summary, γ9δ2 TCRs are an attractive alternative to broadly redirect αßT cells against cancer cells with both an improved efficacy and safety profile compared with currently used αßTCRs.