Key Points• Children with AL given haplo-HSCT after ab T-and B-cell depletion are exposed to a low risk of acute and chronic GVHD and NRM.• The leukemia-free, GVHDfree survival of patients given this type of allograft is comparable to that of HLAmatched donor HSCT recipients.Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of ab T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day 25 to 23 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapsefree survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after ab T-and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120. (Blood. 2017;130(5):677-685)
Angiogenic processes depend on the precise coordination of different cell types and a complex exchange of signals, many of which derive from new specific components of the provisional, angiogenesisrelated, extracellular matrix (ECM). Angiogenesis-associated ECM components thus represent appealing targets for the selective delivery of therapeutic molecules to newly forming tumor vessels. Results of a previous study indicated that a high affinity recombinant antibody (L19) to ED-B, a domain contained in the angiogenesis-associated isoform of fibronectin (B-FN), selectively and efficiently targets tumor vessels. The present study shows that a fusion protein between L19 and interleukin 2 (L19-IL-2) mediates the selective delivery and concentration of IL-2 to tumor vasculature, thereby leading to a dramatic enhancement of the therapeutic properties of the cytokine. By contrast, IL-2 fused to an irrelevant recombinant antibody used as a control fusion protein showed neither accumulation in tumors nor therapeutic efficacy. Tumors in mice treated with L19-IL-2 were significantly smaller compared to those in animals treated with saline, the control fusion protein, or IL-2 alone (P ؍ .003, .003, and .002, respectively). Moreover, no significant differences in size were observed among the tumors from the different control groups (using the control fusion pro- IntroductionDuring tumor progression, the extracellular matrix (ECM) of the normal tissues in which the tumor grows is remodeled through 2 different processes: proteolytic degradation and neosynthesis of ECM components by both neoplastic and stromal cells. These processes generate a "tumoral ECM" that differs quantitatively and qualitatively from the normal tissue ECM and that apparently gives rise to a more suitable environment (inductive or instructive) for tumor progression. [1][2][3] In particular, ECM components modulate vascular cell behavior and angiogenic processes. 4,5 This observation is upheld by the recent report that the majority of messenger RNAs (mRNAs) newly expressed by tumoral endothelial cells encode for ECM proteins. 6 Thus, these provisional ECM components that appear during the angiogenic processes represent an appealing target for the selective delivery of therapeutic molecules to newly forming blood vessels. 7 Furthermore, because new vessel formation is common to all solid tumors, the angiogenesisassociated ECM components can be regarded as pan-tumoral antigens. [8][9][10][11][12] One such ECM component is a fibronectin (FN) isoform, B-FN, which contains an extra FN type III repeat of 91 amino acids, the domain B (ED-B). 13 Because the amino acid sequence of ED-B is identical in mouse, humans, and other mammals, antibodies to this domain react equally well with mouse, human, and other species B-FN. B-FN is detectable only in the stroma of fetal and neoplastic tissues and around newly forming blood vessels, but not in mature vessels. 14,15 Using a radioiodinated human recombinant single-chain Fv (scFv; L19) to the ED-B domain of FN, we demon...
Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder
Key Points Vδ1 and Vδ2 T cells promptly reconstitute in children given haploidentical stem cell transplantation depleted of αβ+ T and CD19+ B cells. Vδ1 cells are expanded in patients experiencing cytomegalovirus reactivation; ZOL potentiates Vδ2 killing against leukemia blasts.
NK and DC reciprocal interactions have only recently been investigated. In this study, we focused on the interplay between NK cells and DC in two models of bacterial infection. Immature monocyte-derived DC were cultured in the presence of live Escherichia coli or bacillus Calmette-Guérin. Upon exposure to either extracellular or intracellular bacteria, DC underwent maturation as assessed by the increased levels of expression of CD80,CD86, and HLA molecules and the de novo expression of CD83 and CCR7. Significant amounts of TNF-alpha and IL-12 were released by DC upon infection, whereas IL-2 and IL-15 were barely detectable in culture supernatants. Both infected and uninfected DC were capable of inducing in fresh autologous NK cells the expression of CD69 and HLA-DR and of inducing cell proliferation. Remarkably, however, infected DC were much stronger inducers of NK cell activation and proliferation than uninfected DC. Thus, after just 24 h of NK/DC coculture, only those NK cells that had been exposed to bacteria-infected DC had acquired the ability to lyse autologous immature DC. In addition, infected DC were more resistant to NK-mediated lysis as a consequence of the up-regulation of HLA class I molecule expression on their surface. This study suggests a regulatory circuit involving NK cells and DC in which DC-induced NK cell activation is effectively enhanced by the presence of pathogens. Activated NK cells, by limiting the supply of immature DC, may then exert a control on subsequent innate and adaptive immune responses.
Purpose: We have shown previously that the MHC class II^negative murine TS/A adenocarcinoma is rejected in vivo if induced to express MHC class II molecules by transfection of the MHC class II transactivator CIITA. In this study, we explored the immunologic basis of tumor rejection and the correlation between histopathology of tumor tissue and immune rejection. Experimental Design: StableTS/A-CIITA transfectants were generated and injected into mice. In vivo cell depletion, immunohistochemistry of tumor tissues, and immune functional assays were done to assess the cellular and immunologic basis of rejection.
IL-21 is an immune-stimulatory four α helix cytokine produced by activated T cells. To study the in vivo antitumor activities of IL-21, TS/A murine mammary adenocarcinoma cells were genetically modified to secrete IL-21 (TS/A-IL-21). These cells developed small tumors that were subsequently rejected by 90% of s.c. injected syngeneic mice. Five days after injection, TS/A-IL-21 tumors showed numerous infiltrating granulocytes, NK cells, and to a lesser extent CD8+ T cells, along with the expression of TNF-α, IFN-γ, and endothelial adhesion molecules ICAM-1 and VCAM-1. At day 7, CD8+ and CD4+ T cells increased together with IFN-γ, and the CXC chemokines IFN-γ-inducible protein 10, monokine induced by IFN-γ, and IFN-inducible T cell α-chemoattractant. The TS/A-IL-21 tumor displayed a disrupted vascular network with abortive sprouting and signs of endothelial cell damage. In vivo depletion experiments by specific Abs showed that rejection of TS/A-IL-21 cells required CD8+ T lymphocytes and granulocytes. When injected in IFN-γ-deficient mice, TS/A-IL-21 cells formed tumors that regressed in only 29% of animals, indicating a role for IFN-γ in IL-21-mediated antitumor response, but also the existence of IFN-γ-independent effects. Most immunocompetent mice rejecting TS/A-IL-21 cells developed protective immunity against TS/A-pc (75%) and against the antigenically related C26 colon carcinoma cells (61%), as indicated by rechallenge experiments. A specific CTL response against the gp70-env protein of an endogenous murine retrovirus coexpressed by TS/A and C26 cells was detected in mice rejecting TS/A-IL-21 cells. These data suggest that IL-21 represents a suitable adjuvant in inducing specific CTL responses.
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