In Vivo Immunomanipulation of Vγ9Vδ2 T Cells with a Synthetic Phosphoantigen in a Preclinical Nonhuman Primate Model

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Abstract
Vγ9Vδ2+ cells represent the major population of γδ T cells in primate blood and react in an MHC-unrestricted fashion to a set of low m.w. nonpeptide phosphoantigens. Two types of structurally related agonists have been discovered so far: the natural phosphoantigens (hydroxydimethyl allyl-pyrophosphate or isopentenyl-pyrophosphate (IPP)) acting directly on Vγ9Vδ2+ TCR and aminobisphosphonates, which block the mevalonate pathway in target cells, leading to accumulation of natural phosphoantigens that in turn activate Vγ9Vδ2+ cells. We demonstrate in the cynomolgus monkey that Vγ9Vδ2 can be manipulated in vivo with bromohydrin pyrophosphate (BrHPP)/Phosphostim, a potent synthetic agonist for which the mechanism of action is similar to natural phosphoantigens. Although of very short half-life, injection of BrHPP leads to strong activation of Vγ9Vδ2, inducing production of a high level of Th1 cytokines. Combination of BrHPP with low-dose rhIL-2 induces specific amplification of effector-memory peripheral Vγ9Vδ2 in blood in a dose-dependant manner. This transient response returns to baseline within 10–15 days. Successive infusions of BrHPP and rhIL-2 induce less vigorous expansions, suggesting a progressive exhaustion of the response. As no toxicity is detected with or without IL-2, this scheme represents a promising immunotherapeutic strategy for induction of systemic Th1 cytokines and massive expansion of γδ T cell subset with antitumor and anti-infectious properties.