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In vivo manipulation of Treg cells
demonstrated that post ECP, Treg levels in mouse and humans are elevated, suggesting that these effects on the Tregs might be a primary mechanism underlying the rela- tive success of this clinical approach.169 Regarding stem cell mobilization, studies in primates and healthy HSCT donors showed an increase in Treg frequency using plerix- afor.171,172 Development of balanced JAK1/JAK2 targeted inhibitors has led to promising clinical results in aHSCT.176 Notably, baricitinib is significantly more potent than rux- olitinib in preventing GvHD and demonstrates high Treg expansion by preserving the JAK3-STAT5 IL-2R path- way.177 Additionally, the Rho kinase inhibitors which down-regulate ROCK1/ROCK2 inhibiting inflammation have also shown promise in suppressing GvHD.178,179 ROCK2 inhibition leads to pSTAT5 upregulation inducing an increase in Tregs.
Cellular “cross-talk” with Tregs can also result in an expansion of this population. For example, host iNKT cells were shown to induce in vivo donor Treg proliferation via IL-4 while preventing lethal aGvHD in mice.182 Subsequently, reports showed that donor iNKT cells diminished aGvHD and cGvHD through the expansion of donor Tregs.183,184 These approaches are currently being examined in clinical trials of a-galactosylceramide, which has been shown to increase numbers of Tregs in model systems by expanding iNKT cells.185
Future perspectives
be particularly effective in inhibiting GvHD.190,191 Allogeneic hematopoietic stem cell transplantation is pri- marily administered to patients with hematologic malig- nancies. There has been increasing usage of checkpoint inhibitors (CI) including PD-1 for the treatment of these cancers and their effect on Tregs remains controversial. Studies have suggested that the PD-L1/PD-1 pathway drives Treg stability/function and expansion.6,192,193 while others have reported Treg inhibition.194,195 Clinical improve- ment of experimental GvHD was associated with increased PD-1 levels on Tregs consistent with the hypoth- esis that this pathway promotes Treg-mediated toler- ance.196 Stimulation of PD-1 on Tregs in hematologic tumors have been reported to promote the inhibition of effector T cells, reducing anti-tumor immune responses.193 Although early reports noted that severe GvHD may result from administering pembrolizumab post HSCT in patients with hematologic malignancies,197 evaluation using CI after PTCy deletion of alloreactive T cells should be considered. In addition to promoting CD8 anti-tumor specific T cells, the success of this therapeutic approach may also depend on direct effects of PD-1 inhibitors on Tregs, since increas- ing or decreasing their numbers/function could positively or negatively modulate anti-tumor immunity. Taken together, since no single prophylactic treatment including adoptive Treg transfer is likely to abolish GvHD, we sug- gest combining in vivo Treg expansion strategies with promising reagents being translated to clinical aHSCT is feasible and could provide a significant advance in the
field. Approaches manipulating Tregs in vivo continue to advance. Systemic administration of IL-2 and other com-
pounds can elevate the peripheral compartment for extend-
ed time-periods without apparent alteration of global immune function. Notably, not all reagents have equivalent efficacy in inducing and maintaining Treg expansion, which
is a result of the specific receptor targeted and reagent per- sistence. For example, administration of modified IL-2 com-
pared with free IL-2 results in greater Treg frequency in
large measure due to prolonging the half-life of the cytokine.45,180,186 This has fostered increasing numbers of
novel IL-2 constructs including fusokines, muteins and IL- 2/receptor fusion proteins.54,181,187,188 A recent study reported
human IL-2 complexed to a human anti-IL2 mAb with in
vivo enhancing activity.189 The development of highly CD25 specific signaling reagents with increased persistence sug-
gests in vivo delivery to selectively target Tregs versus Tconv
may lead to more effective therapeutic application during
disorders where effector cells are present.
To date, approaches targeting Tregs have focused pri-
marily on systemic (vs. local) homeostasis. Local manipu- lation of Tregs might provide an effective strategy for the treatment of widespread (systemic lupus erythematosus, etc.) as well as regional (e.g. GI diseases, encephalitis) inflammation. Treg expansion in the conjunctiva/ocular adnexa can be induced targeting CD25,41 or more potently through CD25 and TNFRSF25 (Copsel et al., unpublished data, 2019). Such strategies may be useful to treat ocular GvHD and uveitis. In the context of HSCT, conditioning using targeted total lymphoid irradiation promotes selec- tive survival of Tregs locally, for example the GI. Subsequent administration of reagents may therefore “selectively” manipulate local intestinal Tregs which could
The Treg compartment can now be manipulated in vivo as a consequence of intentionally targeting identified receptors. Pre-clinical and clinical studies contributed by a large number of laboratories have directly targeted these cells and reported the ability to efficiently augment their numbers and function in vivo. While there is an increasing number of molecules which effectively expand Tregs, for the moment IL-2 is the only FDA-approved compound in use in GvHD clinical trials. It is not surpris- ing that efforts to improve in vivo IL-2 efficacy through the generation of modified IL-2 molecules are currently underway. Other strategies stimulating different signaling pathways promoting Tregs have shown promise in pre- clinical models. Targeting TNF receptors for example, TNFRSF25 alone or together with LD IL-2 has demon- strated extremely potent Treg expansion and improved function. Combination approaches should, therefore, be investigated for potential clinical application.
Acknowledgments
SC: support from a Sylvester Comprehensive Cancer Center research grant for post-doctoral trainees; KVK support from: Kalish Family Foundation, Applebaum Foundation and the Sylvester Comprehensive Cancer Center; RBL support from: the Sylvester Comprehensive Cancer Center, NIH (RO1 EY024484-01) and an SRA from Heat Biologics, Inc. and Pelican Therapeutics. Due to space limitations, the authors sin- cerely regret not being able to cite all of our colleagues’ publica- tions contributing to this field.
Conclusions
haematologica | 2019; 104(7)
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