Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation.

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses. In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), MDSCs (in the donor graft and in the recipient, after allo-HSCT) might mediate immune suppression through multiple mechanisms. However, it remains unclear how MDSCs can be distinguished from their normal myeloid counterparts in the hematopoietic stem cell donor graft and during immune reconstitution after allo-HSCT in the recipient. Our ability to understand their exact role in allo-HSCT is limited by the absence of a specific gene signature or surface markers for identifying MDSCs among myeloid cells and by their plasticity in different microenvironments. According to various studies, MDSCs might induce transplant tolerance and control graft vs. host disease (GVHD), but their impact on the graft vs. tumor effect (GVT) is not fully understood. In fact, we know that MDSCs commonly expand in patients with cancer, and they are thought to promote hematological malignancy progression. However, little is known about whether depleting them might be an effective strategy for enhancing GVT effects. Here, we review data published over the past 40 years on allo-HSCT to delineate the different MDSC subsets, and their abilities to induce transplant tolerance and preserve the GVT effect. This review will provide a basis for determining whether one MDSC subset might be proposed as the most appropriate candidate for cellular therapies, due to its ability to modulate GVHD.

Outcome of patients with Myelofibrosis relapsing after allogeneic stem cell transplant: a retrospective study by the Chronic Malignancies Working Party of EBMT.

Allogeneic Haematopoietic Stem Cell Transplant (allo-HSCT) remains the only curative approach for Myelofibrosis (MF). Scarce information exists in the literature on the outcome and, indeed, management of those MF patients who relapse following transplant. We hereby report on the management and outcome of 202 patients who relapsed post allo-HSCT for MF.

The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years-a report from the EBMT acute leukemia working party.

BACKGROUND: Data comparing fully matched and mismatched-unrelated-donor (M- and mM-URD) allogeneic hematopoietic stem cell transplant (allo-SCT) following reduced intensity conditioning regimens for acute myeloid leukemia are limited. METHODS: We retrospectively compared the outcome of 3398 patients above the age of 50 years who underwent 10/10 M-URD (n = 2567), 9/10 (n = 723), or 8/10 (n = 108) mM-URD allo-SCT for acute myeloid leukemia after reduced intensity conditioning regimen between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. RESULTS: HLA matching had no impact on engraftment (p = 0.31). In univariate analysis, in comparison to 10/10 M-URD, mM-URD was associated with higher incidence of grade II-IV acute graft-versus-host disease (GVHD) (p = 0.0002), similar rates of chronic GVHD (p = 0.138) but increased incidence of its extensive form (p = 0.047). Compared to 10/10 M-URD, patients transplanted in the first complete remission (CR1) with a 9 or an 8/10 mM-URD had decreased 2-year leukemia free (LFS) (p = 0.005) and overall survivals (OS) (56.7, 46.1, and 50.2 %, respectively, p = 0.005), while outcomes were comparable between all groups for patients transplanted beyond CR1. In multivariate analysis, 9/10 versus 10/10 URD was associated with higher non-relapse mortality (HR 1.34, p = 0.001), similar risk of relapse and chronic GVHD and inferior LFS (HR 1.25, p = 0.0001), and OS (HR 1.27, p = 0.0001). There was no difference in adjusted transplant outcomes between 9/10 and 8/10 mM-URD. CONCLUSIONS: Reduced intensity conditioned allo-SCT with a 10/10 M-URD remains the preferable option for AML patients above the age of 50 years. The use of a 9/10 or an 8/10 mM-URD in patients not having a fully matched donor represents an alternative therapeutic option that should be compared to other alternative donor transplant strategies.

Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT.

BACKGROUND: Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown. METHODS: We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria. RESULTS: A combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25%) patients in RIC and 125 (32%) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92%; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29%, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non-relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR ≥ 1.4, p ≤ 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94). CONCLUSIONS: These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL.

Clinical relevance of recipient leukocyte infusion as antitumor therapy following nonmyeloablative allogeneic hematopoietic cell transplantation.

OBJECTIVE: Graft-versus-leukemia effects of donor lymphocytes have been considered to be central to the therapeutic benefit of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for malignant diseases. Surprisingly, some patients who reject donor grafts following nonmyeloablative HCT have sustained remissions of advanced, chemorefractory hematologic malignancies. In murine mixed chimeras prepared with nonmyeloablative conditioning, we previously showed that recipient leukocyte infusions (RLIs) induce loss of donor chimerism and mediate antitumor responses against host-type tumors. We assessed the clinical relevance of our mouse model. METHODS: Mixed chimeric mice were generated by a nonmyeloablative protocol and some of them received host-derived tumor cells and/or RLIs or donor lymphocyte infusion (DLI). We examined chimerism, graft-versus-host disease (GVHD), and tumor survival. RESULTS: RLI is still effective when the leukocytes are obtained from tumor-bearing mice. Established mixed chimerism is required prior to the induced rejection to achieve maximum antitumor effects. The antitumor effects of RLI are not dependent on a specific donor strain or conditioning protocol. In contrast to DLI, RLI leads to donor cell rejection without the risk of GVHD. CONCLUSION: Together, these data reinforce the clinical potential of RLI therapy as a new HCT strategy that does not carry the risk of GVHD.

Maturation of human monocyte-derived dendritic cells (MoDCs) in the presence of prostaglandin E2 optimizes CD4 and CD8 T cell-mediated responses to protein antigens: role of PGE2 in chemokine and cytokine expression by MoDCs.

Prostaglandin E2 (PGE2) acts in synergy with other inflammatory stimuli such as tumor necrosis factor (TNF) to induce the maturation of migratory-type monocyte-derived dendritic cells (MoDCs). However, PGE2 has been reported to inhibit IL-12p70 production by MoDCs and to promote the generation of Th2 T cell responses. We demonstrate here that the addition of PGE2 to TNF for the maturation of MoDCs enhanced CD4 and CD8 T cell proliferative responses to neoantigen and recall antigen, and enhanced Th1-type responses. The increased stimulatory capacity of MoDCs matured with PGE2 was associated with a fully mature, migratory-type MoDC phenotype and more rapid down-regulation of the expression of inflammatory chemokines, with up-regulated expression of the constitutive chemokines TARC and MDC. In addition, although MoDCs matured with TNF and PGE2 selectively produced the inhibitory IL-12p40 subunit at steady state, they were able to produce the bioactive IL-12p70 heterodimer after stimulation with CD40 ligand and/or IFN-gamma. Despite increased IL-6 mRNA expression, MoDCs matured with PGE2 did not overcome the suppressive effects of CD4+ CD25+ T cells in allogeneic mixed lymphocyte reactions. In conclusion, MoDCs matured in the presence of PGE2 display characteristics of more efficient antigen-presenting cells that might be optimal for use in cancer vaccine-based clinical trials.