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S. Copsel et al.
lations is the absence of the precise in situ microenviron- ment wherein individual cell populations differentiate, undergo expansion and mediate effector function. Several established strategies have incorporated the use of micro- bead and antigen-presenting cell (APC)-based technologies to expand Tregs incorporating anti-CD3, CD28, and anti- TNFR family mAbs together with cytokines (e.g. IL-2, TGFβ, and retinoic acid).19 Successful expansion ranging from approximately 100-1300x was reported from starting populations of peripheral blood (CD4+CD127lo/−) and umbilical cord (CD25+) cells.15,20 Notably, employing these Tregs in phase I studies reported no apparent toxicities or adverse effects.15,21
Although Tregs can be induced to expand in vitro, size and purity of the initiating culture, the maintenance of FoxP3 expression and functional activity during culture vary and depend both on starting cell populations and cul- ture conditions. Consistency of reagents from batch to batch also poses challenges for ultimate clinical applica- tion. Generation of a GMP product containing high cell numbers for adoptive therapy requires infrastructure and significant economic investment.22-24 Accordingly, routine- ly generating adequate numbers of functional Tregs in vitro as a readily available adoptive therapy remains transla- tionally challenging.25 Several excellent articles which include discussion of in vitro expansion methods have recently been published and we refer readers to these thorough reviews.26-30 Strategies to manipulate Tregs in vivo have and continue to be examined to circumvent the prac- tical and economic considerations that limit the feasibility of in vitro approaches. The provocative finding that low- dose IL-2 more efficiently stimulates Tregs versus Tconv
populations has fostered optimism that selective manipu- lation of the FoxP3 compartment in situ can be exploited for clinical benefit. Because the production and expansion of effector versus Tregs is associated with the development of chronic graft-versus-host disease (cGvHD), correction of a Treg:Tconv cell imbalance would have therapeutic ben- efit.31 This review presents a historical overview and sur- vey of experience with in vivo Treg expansion and associ- ated changes in their functional capacity. Pre-clinical and clinical studies designed to augment Treg levels and func- tion in vivo examining therapeutic benefit in the setting of GvHD prevention and therapy will be discussed.
Targeting cell surface receptors for in vivo Treg expansion, function and therapeutic application
Experimentally, a number of molecules expressed on Tregs have been shown to expand natural Tregs and/or augment their functional activity in vivo, including IL-2, several members of the TNFR family (TNFR2/TNF; TNFRSF25/TL1A; OX-40/OX-40L; 4-1BB/4-1BB-L) as well as CD28 and IL-33 to suppress autoimmune responses, allograft rejection and GvHD (Table 1 and Figure 1). While other molecules have been found to modulate Tregs in vivo (e.g. CD45, GITR/GITRL), these are not discussed here because they have not been assessed in GvHD.32-34
IL-2 / CD25
Over the past decade, IL-2 treatment has been the approach most extensively utilized in pre-clinical and
Figure 1. Receptors reported to stimulate Treg expansion in vivo. Targeting CD25, members of the TNFR superfamily, CD45RO, CD28 and ST2 was shown to be an effective approach to increase Treg frequency and/or functionality for their pre-clinical / clinical therapeutic application in autoimmune diseases, solid organ trans- plantation and graft-versus-host disease.
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haematologica | 2019; 104(7)