A First-in-Disease Trial of in Vivo Costimulation Blockade for GvHD Prevention: The Addition of Abatacept to Standard GvHD Prophylaxis Controls Early CD4+ T Cell Proliferation and Is Associated with Low Rates of Severe Acute GvHD

We have shown that costimulation blockade can protect against acute GvHD (aGvHD) in a non-human primate model. We therefore designed a first-in-disease trial of in vivo CD28:CD80/86-directed costimulation blockade with CTLA4-Ig (abatacept) to prevent aGvHD after unrelated-donor HSCT for patients > 12y.  In this trial, 10mg/kg abatacept was administered IV on day -1, +5, +14, +28 in addition to standard prophylaxis with cyclosporine + MTX.

Patient Characteristics and Survival: 10 patients, with a median age of 44.5 y (17-74) were enrolled and treated.  6 received 7/8-matched and 4 received 8/8-matched URD HSCT.  8 received PBSCs and 2 received BM. All received high-intensity conditioning. With a median follow-up of 367 days (262-680), 7 patients are alive and in remission and 2 patients died of relapse.  One patient died, in remission, of trauma-related multi-organ failure > 1yr post-transplant.

Feasibility, Pharmacokinetics and Pharmacodynamics: All 10 patients received all  scheduled abatacept doses, without infusion reactions. The average peak (230.9 +/- 7.4 mg/ml) and trough (45.9 +/- 2.8 mg/ml) abatacept levels, as well as the terminal T_1/2  (19.6 +/- 1.9 days) were similar to healthy controls. Importantly, as has been established in vitro, patients receiving abatacept demonstrated significant inhibition of post-transplant CD4+ T cell proliferation (with >80% reduction of Ki-67+ proliferating CD4+ T cells at d +28 compared to controls not receiving abatacept, Figure 1A).

Engraftment: All patients achieved neutrophil engraftment (median d+16.5) and donor engraftment (100% CD33 chimerism at d+30). Lymphocyte recovery was rapid: Day +100 counts showed ALC = 1053 +/- 259 cells/ml, total T cells = 741 +/- 208 cells/ml, and CD8+ T cells = 381 +/- 99 cells/ml. The Day +100 CD4+ T cells  = 285 +/- 105 cells/ml, not significantly different from historical controls (n = 43) that received CNI/MTX aGvHD prophylaxis without abatacept (262 +/-26 cells/ml).

GvHD: Patients receiving the abatacept-containing regimen had encouragingly low rates of early severe aGvHD:  Two patients developed aGvHD before day +100, with one of these patients (Gr II) progressing to steroid-dependent cGvHD of the liver and one patient (Gr III) with resolution of aGvHD.  The cumulative incidence of grade II-IV and III-IV aGvHD by day +100 was thus 20% and 10%, respectively (Figure 1B). Importantly, there was no Gr IV aGvHD, no patient received salvage therapy for aGvHD, and there were no deaths from aGvHD.

Conclusions: This trial demonstrates, for the first time, the feasibility of adding in vivo T cell costimulation blockade with abatacept for aGvHD prevention. The decreased CD4+ T cell proliferation post-transplant and the encouragingly low rates of early, severe aGvHD suggest that costimulation blockade may be an effective agent for aGvHD prophylaxis and support the conduct of a larger, randomized phase 2 study.