Abstract
Poor and delayed immune reconstitution remains a major stumbling block to successful SCT especially when alternative donors are used. Strategies to selectively remove or inactivate alloreactive cells while leaving the other donor T cell repertoire intact might address this problem. A functional T cell response requires an antigen (Ag)-specific MHC-restricted signal (signal 1) to the T cell receptor (TCR) by an Ag presenting cell (APC) as well as a second, Ag independent costimulatory signal (signal 2) provided in large part by B7 family members on APC to CD28 on T cells. Without signal 2, T cells develop tolerance to the specific Ag. Costimulation can be blocked by either CTLA4-Ig, a fusion of Ig with human CTLA4 (the T cell high affinity B7 ligand) or a combination of humanized IgG2 isotype mutated monoclonal antibodies to the APC molecules B7-1 and B7-2. In 2 pilot studies of patients (pts) undergoing haploidentical SCT, donor T cell replete BM was incubated ex vivo with recipient irradiated peripheral blood mononuclear cells with CTLA4-Ig (pilot 1) or anti-B7-1+anti-B7-2 (pilot 2) to induce alloAg specific tolerance. 19 pts age 7 mos-50 yrs (median 15 yrs) were enrolled on pilot 1 and 5 aged 4–12 (median 6) on pilot 2. 3 pts had congenital BM failure. 21 pts with malignancy, ALL (11), AML(7), NHL(2), MDS(1), were >CR1and 14/21 had progressive disease (PD). Pts received TBI based ablative conditioning. Pts received a median of 3.3x106/kg CD34+ cells (0.5–12.3) containing a median of 2.8x 107/kg CD3+ (0.7–6.8), 1.6x 107/kg CD4+ (0.4–4.1), and 1x107/kg CD8+ (0.2–3.7) T cells. One pt got additional anergized cells for slow recovery and engrafted fully. One AML pt had autologous persistence and graft failure (GF). Evaluable pts engrafted at median 21 d (range, 13–29) with full donor chimerism. Of the 21 evaluable pts, 9 (43%) had findings consistent with acute GVHD graded B (n=4), C (n=4) and D (n=1) despite inconsistent pathology. GVHD symptoms were largely isolated to the GI tract and resolved with observation or moderate steroids. No death was attributable to GVHD. 11 pts died early of a combination of bacterial or fungal infection and/or regimen-related toxicity at a median of 35 d (8–159). Of the remaining 13 pts, the GF pt died after 2nd SCT elsewhere, 1 pt had sudden death d 176 at home and 2 pts with extramedullary AML died d 60 and 149 with PD. One T-ALL pt died of late PD d 1758. All BM failure and 3/14 transplanted with PD survive. All 8 survivors (8/19 < 23 yrs) have 100% performance status at a median of 2423 d (1580–2875). None take medications or have chronic GVHD. 3 pts became CMV Ag + by d 100, (1 was transplanted with CMV), and responded to anti-viral therapy. Unlike many reported approaches to haploidentical SCT, aside from several CVL associated bacteremias, there have been no admissions for opportunistic infection and no late viral infections. All pts have good T cell counts, respond to vaccines and specific Ags and have good immunoglobulin levels. Costimulatory blockade, a method of limiting alloreactivity which leaves the remaining T cell repertoire intact, holds out promise as a method of overcoming alloreactivity while better preserving donor immune function and preserving anti-tumor activity. A new study combining costimulatory blockade and megadose stem cell SCT has been initiated.
CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans