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Translational and clinical advances in aGvHD
involving both pan-T-cell and selective T-cell subset deple- tion for the clinic, reviewed below.
Pan-T-cell depletion - ex vivo TCD of the donor graft has been utilized as a method to prevent GvHD, considering competing risks of relapse and NRM. Methods have includ- ed monoclonal antibodies with or without complement,47-50 immunotoxins,51 and counter flow elutriation.52
Ex vivo TCD was evaluated in a multi-center RCT of TCD grafts versus CNI-based prophylaxis.53 TCD was asso- ciated with lower rates of grade III-IV but not grade II-IV aGvHD, with no change in DFS. Graft failure and increased disease relapse (20% vs. 7%) was a concern, with increased relapse also noted in a seminal registry analysis.54 Other studies also suggested increased rates of graft failure with TCD grafts, ameliorated by ATG or thiotepa conditioning to prevent host immune-mediated graft rejection.
T-cell depletion based on immunomagnetic CD34+ graft selection (to eliminate contaminating immune cells) was evaluated in a single-arm phase II multicenter trial and showed low rates of cGvHD and relapse.55 This was com- pared to CNI-based prophylaxis in a retrospective analysis, where outcomes were similar, with lower rates of cGvHD in the CD34 arm.56 Ex vivo TCD remains the primary mode of transplantation in certain centers, although infectious complications, particularly viral infections, can be problem- atic. To better define optimal GvHD prophylaxis, results from an ongoing RCT of ex vivo TCD versus PTCy with MMF only versus standard CNI-based regimen are eagerly awaited (clinicaltrials.gov identifier: NCT02345850).
(66%), suggesting a lack of efficacy with this approach alone.62 A combinatorial approach using a/β TCD com- bined with CD45RA naïve cell depletion was not much bet- ter, with aGvHD rates in the 58% range.63 Hence, for the moment, this approach remains only investigational.
CD6 depletion - CD6 is a co-stimulatory receptor, predom- inantly expressed on T cells that bind to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on APC and various host tissues and plays an integral role in modulating T-cell activation, proliferation, differentiation and trafficking. CD6 depletion using a monoclonal anti- body (mAb) (anti-T12, CD6) that recognized mature T cells but not other cellular elements (e.g., B, natural-killer [NK] cells, and myeloid precursors) was clinically evaluated in a single arm trial with 112 patients with a grade II-IV aGvHD rate of 18%.48 More recently, itolizumab a humanized anti- CD6 mAb, was evaluated in human xenograft models, sug- gesting that itolizumab can modulate pathogenic Teff activ- ity.64 Itolizumab has been provided fast track status by the US Food and Drug Administration (FDA) for this indication and is undergoing evaluation in a phase I/II study for first- line treatment (with steroids) of severe aGvHD (clinicaltri- als.gov identifier: NCT03763318).
Graft engineering: Treg/Tcon add back strategies - in haploHSCT, in the early 1990s, CD34+ cell selection was used by the Perugia group to generate T-cell depleted peripheral blood progenitor cell grafts. Although GvHD rates were low, there was poor immune reconstitution (IR) and high rates of infection.65 The Perugia group then pio- neered the use of a ‘megadose’ of CD34+ cells to facilitate engraftment and improve IR based on the increased tolera- bility effect of such a dose of CD34+ cells.66 Subsequently, further TCD by negative selection of CD3/CD19+ cells was used. Most recently, CD34+ selection followed by graduat- ed add back of Tregs and conventional T cells (Tcons) (in a 2:1 ratio) have been adopted, with promising early results for enhanced IR and GvL, but aGvHD remains a concern.67 Further iterations of this approach may yield enhanced clin- ical benefit, despite their complexity and cost.
Regulatory T-cell enhancement
Tregs - Tregs are CD4+CD25+Foxp3+ cells which play an important role in immunologic homeostasis and the control of aberrant or overactive immune effectors. Tregs can be derived ‘naturally’ from the thymus (nTregs) or converted from CD4+CD25- cells (inducible or iTregs).6 iTregs require IL-2 and TGF-β to fully develop their suppressive function. Blazar et al. showed that ex vivo activation and expansion of Treg is feasible, with efficacy in murine GvHD models.68 Other approaches have utilized fucosylation69 and TL1A/TNFRSF25 stimulation70 for ex vivo Tregs. In clinical transplantation, they have confirmed the feasibility and safety of ex vivo Treg expansion and adoptive transfer, with preliminary clinical efficacy for aGvHD prevention in both cord71 and haploHSCT.67 However, concerns about stability of expanded Tregs has been a barrier to translation into the clinic.
Invariant natural killer T cells - invariant NK T (iNKT) cells are a rare T-lymphocyte subset which co-express both T- and NK-cell markers and are considered a bridge between innate and adaptive immunity. Their semi-invariant TCR recognizes glycolipid antigens presented by the major his- tocompatibility complex (MHC) class I-like molecule Cd1d. Despite their rarity, they have strong immunomod- ulatory functions through the secretion of IL-4 and IL-10,
Beyond pan-T-cell depletion, subset-selective T-cell depletion and modulation strategies to ameliorate GvHD without compromising GvL effect by using antibodies with narrow specificities has become an area of great interest.50 Depletion of CD5+ T cells51 and CD8+ T cells were tried in the 1990s, but abandoned primarily due to higher rates of relapse. Other novel strategies are discussed below.
a/β T-cell depletion - the majority of T lymphocytes express a/β T-cell receptors (TCR), while γ/d TCR are expressed by 2-10% of circulating T cells. γ/d T cells have important innate immune functions including rapid release of cytokines, and killing of tumor and virally infected cells without inducing GvHD.57 They may have an important role in GvL effect and the preservation of NRM. Selective depletion of a/β T cells would preserve NK cells as well as γ/d T cells. In a prospective study of 80 pediatric patients with acute leukemia, a/β TCD was studied with encourag- ing GRFS of 70%.58 Ongoing studies are further evaluating this approach in adult and pediatric populations, including a CNI-free GvHD prophylaxis strategy for acute leukemia patients undergoing 1-2 locus MMUD MAC HSCT (clinical- trials.gov identifier: NCT03717480).
CD45RA (naïve) T-cell depletion - conceptually, it is naïve T cells in the donor allograft that are primarily alloreactive. In a study in healthy individuals, the bulk of allo-HLA reactiv- ity was derived from subsets enriched for naïve T cells.59 Hence, removal of CD45RA+ naïve T cells from the donor graft could help prevent aGvHD alloreactivity. The CD45RA− target fraction contains effector and central mem- ory T cells that show preserved reactivity to common viral and fungal pathogens.60 In a two-step immunomagnetic bead procedure for naïve TCD, Bleakley et al.61 reported on a first-in-human single-arm trial (n=35) for patients with acute leukemia transplanted with HLA-matched related donors. Although 34 of 35 patients engrafted with lower rates of cGvHD, rates of aGvHD remained relatively high
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