Rapid Lymphocyte Recovery And Intravenous Immunoglobulin Independence In Children With Severe Combined Immunodeficiency (SCID) Undergoing Allogeneic Stem Cell Transplantation With Reduced Intensity Conditioning (RIC)
Biology of Blood and Marrow Transplantation
Adoptive transfer of alloanergized donor T cells is a simple approach to augment immune reconstitution while limiting GvHD after TCD haploidentical (haplo) HSCT. However the optimal dose and impact on antigen-specific immune reconstitution remain unknown. On a new study, 7 adults and 4 children received fractionated TBI (12Gy, n 5 5) or melphalan (140mg/m 2 , n 5 6), fludarabine, thiotepa and ATG followed by CD34-selected peripheral blood stem cells (median 9.4 CD34 1 and 0.02 CD3 1 Â10 6
... kg) from haplo donors without further GvHD prophylaxis. All engrafted rapidly with full donor chimerism. Using an adaptive trial design, 10 pts received alloanergized donor PBMC (generated by co-culture with irradiated stimulator PBMC and humanized anti-B7.1 and -B7.2 antibodies resulting in a median 6-fold reduction in alloresponses) in escalating dose (Ds) cohorts: Ds1, 10 3 CD3 1 cells/kg (n 5 4), Ds2 10 4 /kg (n 5 3) and Ds3 10 5 /kg (n 5 3). 3 pts developed Gr 2-4 acute GvHD, (1 Ds 2, 2 Ds3), all responding to treatment. 0/7 evaluable pts developed chronic GvHD. 7/11 pts are alive (median f/u 8 months). 3 pts died from regimen related toxicity before D1100 and 1 from post-operative bleeding (D1738). 2 pts relapsed. CD4 T cell recovery was faster and functional pathogen-specific CD4 and CD8 T cells became detectable earlier in pts receiving higher doses of alloanergized PBMC. Median time to CD4 ct .100/ml was 9, 3 and 2 months and CMV or VZV-specific IFN-g 1 T cells became detectable at 7.5, 3 and 2.5 months at Ds 1,2 and 3 respectively. The effector memory phenotype of recovering T cells was consistent with peripheral expansion of infused alloanergized donor T cells. 5 pts reactivated CMV before alloanergized PBMC infusion, but no new episodes of CMV reactivation or CMV disease occurred after infusion. 2 pts had large expansions of CMV-specific CD4 and CD8 T cells (up to 10%) before D1100, coinciding with clearance of CMV viremia. One Ds3 pt had adenoviremia despite high dose cidofovir, resolving with expansion of infused donor T cells. 2 Ds1 pts developed late viral infections: 1 reactivated EBV, and 1 developed disseminated VZV resolving after VZV-specific T cells became detectable. No late viral infections occurred in assessable Ds2/3 pts. These early data support a contribution of alloanergized donor PBMC to quantitative and qualitative immune reconstitution after TCD haploHSCT. Further recruitment will determine the optimal dose that can be safely administered in this setting.