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M. Gooptu and J. Koreth
as well as providing active immunologic surveillance against cancer.72 Murine models suggested that iNKT cells have a protective effect against GvHD without impairing the GvL effect. This occurs in part via a switch of donor T cells to a Th2 cytokine profile and/or IL-4 dependent Treg expansion.73,74 Observational studies suggest lower acute and chronic GvHD with improved iNKT cell reconstitu- tion. Clinical translation has involved RIC HSCT utilizing total lymphoid irradiation plus ATG (TLI-ATG) condition- ing (offering iNKT expansion in murine models) with promising outcomes,75 as well as more direct ex vivo expansion and adoptive iNKT transfer peri-transplant, where clinical data are eagerly anticipated. KRN7000 (syn- thetic derivative of a-galactosylceramide and a CD1d lig- and) when embedded in a lipid bilayer constitutes RGI- 2001or REGiMMUNE which can expand FoxP3+ Tregs via iNKT cells in mice to reduce aGvHD lethality.76 Recently a phase IIa trial of a combination of Siro and RGI-2001 showed lower incidence of overall and severe aGvHD in responders compared to non-responders.77 Although promising, iNKT targeted approaches have not been widely adopted for the moment and more mature data are awaited.
Cytokine targeting
Tocilizumab - interleukin-6 (IL-6) is a key inflammatory cytokine in the early pathogenesis of aGvHD in murine models.78 A logical next step was to investigate the role of IL-6 blocking agents in preventing aGvHD. Tocilizumab is a humanized mAb against the IL-6 receptor (IL-6R). Based on promising phase II data,79 a placebo-controlled phase III study from Australia was reported, which, however, showed no significant difference in grades II-IV or III-IV aGvHD.80 This is a salient reminder that, given the complex pathophysiology of aGvHD, with crosstalk between myri- ad cytokines and immune effector cells, it is possible that targeting multiple cytokine pathways will be required for efficacy.
Targeting T-cell co-stimulatory pathways
As mentioned previously, following initial engagement of an APC with the TCR, a number of secondary co-stim- ulatory signals come into play which are necessary to com- plete alloreactive T-cell activation, proliferation and even- tual development of aGvHD. CD28 is a co-stimulatory receptor while CTLA-4 is a co-inhibitory receptor on the T cell, both of which bind to B7-1/CD80 and B7-2/CD86 lig- ands on APC. CTLA-4-Ig (abatacept) is the soluble extra- cellular portion of CTLA-4 complexed with immunoglob- ulin heavy chain which blocks CD28/CTLA-4 (CD28>CTLA-4) co-stimulation with an eventual T-cell inhibitory signal. Blazar et al. showed in murine models that blockade of the CD28/CTLA-4 and CD80/CD86 interaction reduced aGvHD lethality.81 Following a promis- ing feasibility study, Kean et al. then tested abatacept added to SOC versus SOC in a phase II RCT with 8/8 and 7/8 HLA-matched donors. There was significant reduction in grades III-IV aGvHD in the abatacept arm with improved OS82 leading to FDA breakthrough designation for this drug. To avoid the undesirable effect of concomitantly blocking inhibitory pathways, more selective approaches to CD28 blockade are being investigated. FR104, an antag- onistic CD28-specific pegylated-Fab' has shown promise with and without Siro in non-human primate models, with the caveat that a worrying inhibitory effect was seen on
the INF-γ axis with deaths secondary to sepsis.83 The mod- ulation of co-stimulatory/inhibitory pathways is one of the important new frontiers in aGvHD prevention.
These prophylactic strategies, along with the level of evi- dence supporting them, are summarized in Table 1.
Advances in acute graft-versus-host disease therapy
Systemic steroids, while not FDA-approved for this indi- cation, remain a cornerstone of the initial treatment of moderate-severe aGvHD. In a seminal study, Blazar et al. showed that first-line therapy of aGvHD with corticos- teroids (60 mg daily followed by an 8-week taper) resulted in response rates of 50% and 1-year survival of 53%.84 Higher doses of steroids did not result in better outcomes. In a study comparing 10 mg/kg to 2 mg/kg of methylpred- nisone, both resulted in transplant mortality of 30% at one year with no improvement in aGvHD responses at higher doses.85 SR-aGvHD treatment remains a difficult problem, with 6-month survival in the 50% range, and long-term survival of only 5-30%.86 Stratification systems such as the Minnesota risk score that take into account patterns of aGvHD by target organ involvement can further refine the prediction of transplant-related mortality, and are being considered in clinical trial risk stratification.84 Finally, even when aGvHD is controlled, patients often succumb to infections exacerbated by additional immunosuppressive therapies. Novel therapies are, therefore, a critical unmet need. Here we outline some of the more promising approaches currently available or in early translation to the clinic.
Cytokine pathways
JAK-STAT pathway - the Janus Kinases (JAK) are intracel- lular tyrosine kinases investigated as GvHD therapeutic targets given their important role in cytokine signaling and effects on immune effector cells. In murine models, the role of IFNγ on T-lymphocyte trafficking to GvHD target organs (particularly the GI tract) via CXCR upregulation was studied. Inhibition of interferon (IFN)γR signaling via JAK1/JAK2 inhibitors resulted in decreased CXCR3 expres- sion and altered Teff trafficking to target organs, reducing GvHD.87 Ruxolitinib (Rux) is a potent oral JAK-1/JAK-2 inhibitor. In a proof of concept study, Rux reduced Teff proliferation and activity, increased Tregs and decreased cytokine production, with excellent responses in six SR- aGvHD patients.88
A retrospective survey of off-label Rux in SR aGvHD documented overall response rate (ORR) of 81.5% (com- plete responses [CR] 46%). Cytopenias and cytomegalovirus (CMV) reactivation were seen.89 A phase II single-arm multicenter study of Rux (REACH-1) in 71 patients documented ORR at 28 days of 54.9% (complete remission/CR, 26.8%), irrespective of aGvHD grade and steroid refractoriness.90 In addition to cytopenias and CMV reactivation, serious bacterial infections were reported. The phase III RCT of Rux versus investigator’s choice for SR aGvHD has now been reported (REACH-2). Rux was superior in terms of ORR; however, there was no differ- ence in cumulative incidence of 18-month NRM.91 Infections and cytopenias remain limiting toxicities. The FDA has approved Rux for SR aGvHD.
In contrast, failure of the selective JAK1 inhibitor itaci-
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haematologica | 2020; 105(11)