Overexpression of survivin in BCP-ALL identifies patients with a high risk of early relapse. Upon confirmation in a prospective analysis, survivin expression may, in the future, serve to further refine treatment stratification with intensification of therapy in those patients prone to relapse.
For effective immunotherapy, maintaining the frequency and cytotoxic potential of effector cells is critical. In this context costimulation via the CD70/CD27 pathway has been proven essential. CD70 has been reported to be expressed to varying degrees on malignant B cells. However, in B cell precursor acute lymphboblastic leukemia, the most common childhood malignancy, the role of CD70 in stimulation of antileukemic T cell responses has so far not been delineated. Herein we demonstrate that in B cell precursor acute lymphboblastic leukemia expression of CD70 is low but can be induced upon blast activation via CD40. Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity. Modulation of the CD70/CD27 pathway may thus represent a novel therapeutic approach for augmenting magnitude and quality of the antileukemic response in B cell precursor acute lymphboblastic leukemia.
Previous studies on apoptosis defects in acute lymphoblastic leukemia (ALL) have focused on chemotherapy-induced, primarily mitochondrial death pathways. Yet, immunologic surveillance mechanisms including sensitization to apoptotic signals mediated via the death receptor CD95 might contribute to leukemic control. Here, we show that primary B-cell precursor ALL cells from children escape from receptor-dependent cell death in 2 ways:Resting ALL blasts are protected from receptor-mediated apoptosis due to the absence of CD95 surface expression. However, even though CD40 ligation results in up-regulation of CD95, ALL blasts, unlike normal B cells, remain resistant to apoptosis. We show that this apoptosis resistance involves the selective upregulation of the short isoforms of the caspase-8 inhibitor c-FLIP acting directly at the CD95 receptor level.
IntroductionAcute lymphoblastic leukemia (ALL) in children is a malignant disease with a good overall prognosis. Treatment failure in those patients who suffer relapse has to a large part been attributed to drug resistance and defects in apoptosis. Consequently, investigations on the deregulation of apoptosis in ALL have primarily focused on chemotherapy-induced pathways. 1,2 Yet immunologic surveillance also contributes to long-term survival. 3,4 The capacity of mature normal B cells to respond to CD40 ligation by up-regulation of the CD95 (Fas/APO1) death receptor is critical for their susceptibility to immunologic control. 5-7 Primary B-cell precursor ALL blasts (BCP-ALLs) lack CD95 expression and are resistant to CD95-mediated cell death. 8 Although BCP-ALL blasts express CD40 to variable degrees, there is no information on CD40-dependent modulation of blast sensitivity to apoptotic signals. 9 Death receptor-mediated proapoptotic signals are transmitted via the so-called death-inducing signaling complex (DISC) formed upon oligomerization of CD95 by interaction with its ligand. 10 The oligomerized death domains (DDs) of the receptor associate with the cytoplasmic adapter molecule FADD with subsequent recruitment of procaspase-8 (FLICE) into the DISC. The apoptotic cascade is then initiated by autocatalytic cleavage of procaspase-8 and release of the active enzyme into the cytoplasm. The FLICE inhibitory protein (c-FLIP) can bind to the DISC and interfere with receptor-induced apoptosis. 11 c-FLIP occurs in 3 different isoforms as a result of alternative splicing: 2 short isoforms, c-FLIP Short (27 kDa) and c-FLIP Raji (26 kDa), and a long form c-FLIP Long (55 kDa). 12,13 While the short isoforms, thereafter called c-FLIP S and c-FLIP R , comprise only 2 death effector domains (DEDs) critical for interaction with the DISC, the long isoform contains an additional catalytically inactive C-terminal caspaselike domain. Depending on its expression level, c-FLIP L can serve as a dual regulator with both proapoptotic and antiapoptotic function. 14,15 Thus, it has been shown in adult T-cell leukemia that it is the equilibrium between FLIP and caspase-8 that regulates suscepti...
MHC class II deficiency is a rare and fatal form of primary combined immunodeficiency caused by a lack of T-cell-dependent humoral and cellular immune response to foreign antigens, which can only be cured by allogenic stem cell transplantation. In the literature search, we identified 68 cases of HSCT in MHC class II deficiency in the last 14 yr. Pre- and post-transplant MHC class II deficiency is complicated by overwhelming viral infections, a high incidence of GvHD, and graft failure with a poor overall survival rate below 50%. We report an eight-month-old boy presenting with severe respiratory infections and chronic diarrhea, whose sister died at the age of four yr from septicemia. MHC II deficiency was caused by an RFXANK-mutation and treated successfully by 4/6 mismatched unrelated CBT after a myeloablative conditioning regimen based on anti-thymocyte globulin, busulfane, fludarabine, and cyclophosphamide. At present, our patient is well with full immune reconstitution 3(4/12) yr after CBT. CB may represent an alternative source of stem cells for children with MHC class II deficiency without a suitable donor.
Summary
Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow‐up of ten patients diagnosed with relapsed or refractory mature B‐cell Non Hodgkin Lymphoma (B‐NHL), Burkitt leukaemia (B‐AL) or pre B‐acute lymphoblastic leukaemia (pre B‐ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti‐CD3 x anti‐CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo‐SCT, n = 6) to induce sustained long‐term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo‐SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow‐up. The other patients still maintain CR with a current overall survival of 874–1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients.
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