In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and European Medicines Agency (EMEA) approved. Although their mechanisms of action in vivo is not fully elucidated, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is presumed to be a key effector function. A substantial role of ADCC has been demonstrated in vitro and in mouse tumor models. However, a direct in vivo effect of ADCC in tumor reactivity in humans remains to be shown. Several studies revealed a predictive value of FcγRIIIa-V158F polymorphism in monoclonal antibody treatment, indicating a potential effect of ADCC on outcome for certain indications. Furthermore, the use of therapeutic antibodies after allogeneic hematopoietic stem cell transplantation is an interesting option. Studying the role of the FcγRIIIa-V158F polymorphism and the influence of Killer-cell Immunoglobuline-like Receptor (KIR) receptor ligand incompatibility on ADCC in this approach may contribute to future transplantation strategies. Despite the success of approved second-generation antibodies in the treatment of several malignancies, efforts are made to further augment ADCC in vivo by antibody engineering. Here, we review currently used therapeutic antibodies for which ADCC has been suggested as effector function.
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers. PD-L1 was increased in relapsed ALL patients (n=11) and in ALLs refractory to Blinatumomab (n=5). Exhaustion markers (PD-1, TIM-3) were significantly higher on patients' T cells compared to physiologic controls. T-cell proliferation and effector function was target-cell dependent and correlated to expression of co-signaling molecules. Blockade of inhibitory PD-1-PD-L and CTLA-4-CD80/86 pathways enhanced T-cell function whereas blockade of co-stimulatory CD28-CD80/86 interaction significantly reduced T-cell function. Combination of Blinatumomab and anti-PD-1 antibody was feasible and induced an anti-leukemic in vivo response in a 12-year-old patient with refractory ALL. In conclusion, ALL cells actively regulate T-cell function by expression of co-signaling molecules and modify efficacy of therapeutic T-cell attack against ALL. Inhibitory interactions of leukemia-induced checkpoint molecules can guide future T-cell therapies.
Summary:PCR; minisatellite regions; allogeneic bone marrow transplantation It still remains unclear whether patients with mixed hematopoietic chimerism (MC) after allogeneic bone marrow transplantation (allo-BMT) have an increasedAt present allogeneic BMT (allo-BMT) treatment regimens risk of developing relapse or graft failure. To address are considered to be of advantage in particular malignant this question, we monitored the individual dynamics of and non-malignant diseases. [1][2][3] The success of this treatchimerism after allo-BMT in pediatric patients within ment modality is mainly affected by relapse or graft rejeca prospective case control study. The individual ratio of tion. Factors responsible for relapse and/or graft rejection donor to recipient peripheral white cells was determined may be insufficient conditioning regimens or a deficient by quantification of genomic variable number of tangraft-versus-leukemia (GVL) effect due to decreased dem repeats (VNTRs) with a polymerase chain reaction amounts of donor effector cells or to their functional inef-(PCR) approach. Within the study period from 1 Janufectiveness. In order to evaluate the individual risk for ary 1994 until 1 July 1996 we investigated 50 sequences relapse or graft rejection in correlation to the chimerism of 46 pediatric patients after allo-BMT (32 with maligstatus after allo-BMT, various studies on this subject have nant, 18 with nonmalignant diseases). We found combeen performed previously. [4][5][6][7] Several studies on patients plete chimerism (CC) in 34/50 cases, MC in 12/50 folsuffering from severe aplastic anemia (SAA) or chronic low-ups and 4/50 patients revealed autologous recovery myelogenous leukemia (CML) gave evidence that the risk (AC). Eight of 12 patients with MC showed increasing of relapse or graft failure was increased when MC was autologous patterns and subsequently relapsed or detectable after allo-BMT. 8,9 However, the prognostic value rejected their graft, 3/12 showed decreasing amounts of to predict relapse after MC detection for patients with acute recipient DNA and turned to CC upon further followleukemias remains controversial. 4,9,10 The conflicting up. One patient of 12 who had severe combined results in the literature might be explained on the basis of immunodeficiency (SCID), attained engraftment with a the experience that relapses from acute leukemias generally stable MC pattern. Three patients of 34 with CC develop within a shorter time period in comparison to cases relapsed lacking a transitional MC interval. However, with chronic leukemias. Therefore, studies with relatively the time span between last CC confirmation and relapse long intervals in patient follow-up may have missed the in each of these three patients was 6 months or longer.critical and transient stage of MC. The hypothesis of a critiWe suggest that these patients also developed a stage of cal and transient stage of mixed chimerism was tested transitional MC but that the critical timepoint of molwithin a prospective study of patients a...
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