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

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.

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…Similar observations had been made in nonhuman primates, through either activation with BrHPP/IL2 alone 15,46 or in antituberculous vaccine trials. 52 The underlying molecular basis of this process still remains unknown but could conceivably be attributed to inadequate activation conditions.…”

“…into non-human primates, BrHPP can activate circulating cd cells, despite its extremely short half-life (only a few minutes long). 46 The half-life of zoledronate, in contrast, is far longer (146 h). Whichever stimulus is utilized to induce cd T cells, the kinetics of the ensuing proliferation of cd T cells in human blood typically peaks between days 6 and 8, and the amplitude of the proliferative response directly relates to the presence of IL-2 and the dose of BrHPP or bisphosphonate.…”

“…Most specifically in regard to these lymphocytes, the antigen-driven activation of these cells leads to progressively decreased responses to subsequent stimulations, or tachyphylaxis. 38,46 Dependence on IL-2 for cd cell activation in vivo The use of IL-2 in cancer immunotherapy has been widely debated, owing to this cytokine's intrinsic toxicity. In spite of this toxicity, several conditions can be treated with low-dose IL-2-based regimens, such as renal and prostate carcinomas.…”

Select Plant Tannins Induce IL-2Rα Up-Regulation and Augment Cell Division in γδ T Cells

“…Though expansion of V␦2 T cells in vivo is clearly demonstrated using these new drugs, the benefit of these expanded cells on host defenses is not fully understood due to a minimal or nonexistent response in non-primate animal models (19). Additional caveats for the clinical use of phosphoantigen-based drugs include the requirement for large amounts of agonist (20), induction of rapid cell anergy to treatment (20), and activation of only the V␦2 subset, which must then traffic to the tumor or infection to be effective (8,12,20,21).…”

Lymphocytes Tγδ en cancérologie

“…Les patients non répondeurs aux PAg ou aux ABP représentent un de ces obstacles. Des hypothèses ont été formulées pour expliquer cette absence de réponse et sont à l'étude : l'induction d'une anergie par des lymphocytes T régula-teurs [25], l'existence d'une anomalie des T Vγ9Vδ2 ou l'épuisement des sous-populations T Vγ9Vδ2 mémoires [26] chez des patients cancéreux. Pour pallier les difficultés d'expansion des T Vγ9Vδ2, des essais en présence de cytokines comme l'IL-15 [14] ou l'IL-21 [27] sont évalués, mais une voie particulièrement prometteuse semble celle de leur costimulation par des cellules dendritiques.…”