Effect of Clinically Relevant Immunosuppressants on Viral Specific T-Cell (VST) Function

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Immunocompromised patients suffer significant morbidity and mortality secondary to viral infections. Virus specific T-cells (VSTs) are safe and effective in treating CMV, EBV, BK, and ADV infections following hematopoietic stem cell and solid organ transplantation . Often, these patients are on immunosuppressive medications (IS), which may mechanistically impair T-cell function or have unknown impact on treatment efficacy. We hypothesized that in vitro exposure of VSTs to various clinically relevant IS could act as a proxy for VST function in vivo , and begin to inform clinical practice and shape future investigations. To assess in vitro VST viability and IFNγ secretion after exposure to IS. Two VST products were cultured in recovery media for 7 days, then stimulated with viral pepmix (CMV and ADV) with or without concomitant IS exposure (ruxolitinib, belumosudil, tocilizumab , infliximab , emapalumab , or abatacept) at varying concentrations. Intracellular flow cytometry captured viability and IFNγ expression at 5- and 72-hour exposure timepoints. Significance testing performed with Mann-Whitney U, threshold p<0.05. After stimulation with viral pepmix ± IS, VST viability was similar across conditions at 5-hour timepoint. At 72-hours, while there were no statistically significant differences, ruxolitinib (± pepmix stimulation) and belumosudil (+pepmix) appeared to negatively impact viability. No other clear trends were appreciated. (Figure 1) After stimulation, IFNγ expression at 5-hour timepoint was similar across conditions. At 72-hours, while there were no statistically significant differences, ruxolitinib appeared to negatively impact VST IFNγ expression. No other clear trends were appreciated. (Figure 2) VST stimulated with viral pepmix in vitro retained viability and IFNγ expression for a majority of IS tested. However, initial results suggest ruxolitinib may impact both viability and IFNγ secretion, and belumosudil may have a negative impact on viability. Additional, higher-powered studies are necessary to further characterize these trends. However, this data supports existing clinical practice of ruxolitinib use being exclusionary for VST infusion, and concurrent use of the other tested IS permitted with VST therapy though caution with belumosudil may be prudent. Additional studies with direct measures of in vitro cytotoxicity may be beneficial to further elucidate IS impact on VST function.

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