IL2 enhances ex-vivo expanded regulatory T cell persistence after adoptive transfer

Abstract

As regulatory T cell (Treg) adoptive therapy continues to develop clinically, there is a need to determine which immunomodulatory agents pair most compatibly with Tregs to enable persistence and stabilize suppressor function. Prior work has shown that mechanistic target of rapamycin (mTOR) inhibition can increase stability of thymic Tregs. In this study we investigated the transcriptomic signatures of ex-vivo expanded Tregs after adoptive transfer in the setting of clinically relevant immunosuppression using a non-human primate (NHP) model as a prelude to future transplant studies.Here, we found that adding interleukin-2 (IL2) to rapamycin in vivo supported a logarithmic increase in the half-life of adoptively transferred CFSE-labeled, autologous NHP Tregs, effectively doubling the number of cells in the peripheral blood Treg compartment compared to Treg infusion with rapamycin alone. Using single cell transcriptomics, we found that transferred ex-vivo expanded Tregs initially exhibit a gene expression signature consistent with an activated state. Moreover, those cells with the highest levels of activation also expressed genes associated with p53-mediated apoptosis. In contrast, transferred Tregs interrogated at Day +20 post-transfer demonstrated a gene signature more similar to published profiles of resting Tregs.Together, these preclinical data further support combining IL2 and rapamycin in vivo as adjunctive therapy for ex-vivo expanded adoptively transferred Tregs and suggest that the activation status of ex-vivo expanded Tregs is critical to their persistence.

Non-human Primate Regulatory T Cells and Their Assessment as Cellular Therapeutics in Preclinical Transplantation Models

“…Concurrent IS therapy markedly increases the survival of adoptively-transferred autologous Tregs in the peripheral blood and LNs. Labeled autologous Tregs persist longer in monkeys given rapamycin and in greater numbers compared to nonimmunosuppressed conditions at least 50 days post-infusion (Furlan et al, 2020). Low dose IL-2 together with rapamycin further prolongs the half-life of adoptively-transferred Tregs in NHPs, with detection of labeled cells in the periphery up to 84 days after infusion.…”

“…This phenomenon could potentially be alleviated by systemic IL-2 administration. Thus, Furlan et al (2020) found that, in non-transplanted monkeys, adding low dose IL-2 (1 million units/m 2 /day) to rapamycin in vivo (target trough level: 5-15 ng/ml) promoted a logarithmic increase in the halflife/persistence of adoptively-transferred, autologous NHP Treg, in effect doubling the number of stable circulating Treg compared with Treg infusion in combination with rapamycin alone. Yamada et al (2015) examined the influence of systemic IL-2 on T cell alloreactivity and the maintenance of tolerance to MHC mis-matched kidney allografts induced in cynomolgus macaques via mixed hematopoietic cell chimerism.…”

Precision sirolimus dosing in children: The potential for model-informed dosing and novel drug monitoring

“…It subsequently declines in old age (Simon et al, 2015). Beyond the effects of these genes, patients may have several transcriptomic (Furlan et al, 2020), proteomic (Cohen Freue et al, 2013;Levitsky et al, 2013), metabolomic [reviewed in Supplementary Table S1 of McCune et al (2021a)], and lipidomic (Liggett et al, 2022) characteristics that could influence the effectiveness and toxicity of transplantation and/or sirolimus. For example, metabolomics can offer discoveries yielding new insights into how metabolites (here, endogenous, not sirolimus metabolites) influence gut physiology, organ function, and immune function (Wishart, 2019).…”