An unprespecified interim analysis of results from a phase 1–2 study of gene therapy for sickle cell disease shows resolution of severe vaso-occlusive events in 25 patients who could be evaluated. In ...the 24 months before enrollment, these patients had a median of 3.5 severe vaso-occlusive events per year.
Two patients, one with transfusion-dependent β-thalassemia and the other with sickle cell disease, received autologous CD34+ cells edited with CRISPR-Cas9 targeting of
BCL11A
. Their clinical course ...over the following 16 to 18 months supports further experimental testing of CRISPR-Cas9 gene editing to treat these diseases.
Summary
Although Dara–VCD (daratumumab–bortezomib–cyclophosphamide–dexamethasone) has revolutionized the treatment of newly diagnosed Amyloid Light chain (AL) amyloidosis, patients with stage IIIb ...disease were excluded in the pivotal trial. We performed a multicentre retrospective cohort study to investigate the outcomes of 19 consecutive patients treated with Dara–VCD front‐line therapy who had stage IIIb AL at diagnosis. More than two thirds presented with New York Heart Association Class III/IV symptoms, and had a median of two organs involved (range, 2–4). The haematologic overall response rate was 100%, with 17/19 patients (89.5%) achieving a very good partial response (VGPR) or better. Haematologic responses were achieved rapidly, as evidenced by 63% of evaluable patients with involved serum free light chains (iFLC) < 2 mg/dl and the difference between involved and uninvolved serum free light chains (dFLC) <1 mg/dl at three months. Among 18 evaluable patients, 10 (56%) achieved a cardiac organ response and six (33%) cardiac VGPR or better. The median time to first cardiac response was 1.9 months (range, 0.4–7.3). At a median follow‐up of 12 months for surviving patients, estimated one‐year overall survival was 67.5% 95% confidence interval (CI), 43.8–84.7. The incidence of grade 3 or higher infections was 21%, with no infection‐related mortality thus far. In summary, Dara–VCD has a promising efficacy and safety profile in stage IIIb AL, and should be studied in prospective trials.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The Programmed Death-1 (PD-1) immune checkpoint pathway may be usurped by tumors, including diffuse large B-cell lymphoma (DLBCL), to evade immune surveillance. The reconstituting immune landscape ...after autologous hematopoietic stem-cell transplantation (AHSCT) may be particularly favorable for breaking immune tolerance through PD-1 blockade.
We conducted an international phase II study of pidilizumab, an anti-PD-1 monoclonal antibody, in patients with DLBCL undergoing AHSCT, with correlative studies of lymphocyte subsets. Patients received three doses of pidilizumab beginning 1 to 3 months after AHSCT.
Sixty-six eligible patients were treated. Toxicity was mild. At 16 months after the first treatment, progression-free survival (PFS) was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point. Among the 24 high-risk patients who remained positive on positron emission tomography after salvage chemotherapy, the 16-month PFS was 0.70 (90% CI, 0.51 to 0.82). Among the 35 patients with measurable disease after AHSCT, the overall response rate after pidilizumab treatment was 51%. Treatment was associated with increases in circulating lymphocyte subsets including PD-L1E-bearing lymphocytes, suggesting an on-target in vivo effect of pidilizumab.
This is the first demonstration of clinical activity of PD-1 blockade in DLBCL. Given these results, PD-1 blockade after AHSCT using pidilizumab may represent a promising therapeutic strategy in this disease.
The development of malignant disease might be seen as a failure of immune surveillance. However, not all tumors are naturally immunogenic, and even among those that are immunogenic, the uncontrolled ...rapid growth of a tumor may sometimes out-run a robust immune response. Nevertheless, recent evidence suggests that mechanisms of tolerance that normally exist to prevent autoimmune disease may also preclude the development of an adequate antitumor response and that tumors themselves have the ability to thwart the development of effective immune responses against their antigens. A major challenge has been to develop approaches to breaking this tolerance in tumor-bearing hosts, and recent advances in our understanding of antigen presentation and tolerance have led to some promising strategies. An alternative approach is to use T cells from nontumor-bearing, allogeneic hosts in the form of lymphocyte infusions, with or without hematopoietic cell transplantation. Immunotherapy may occur in this setting via the response of nontolerant, tumor antigen-specific T cells from nontumor-bearing hosts or via the powerful destructive effect of an alloresponse directed against antigens shared by malignant cells in the recipient. Approaches to exploiting this beneficial effect without the deleterious consequence of graft-versus-host disease in allogeneic hematopoietic cell recipients are discussed.
In multiple myeloma (MM), frequent mutations of NRAS, KRAS, or BRAF are found in up to 50% of newly diagnosed patients. The majority of the NRAS, KRAS, and BRAF mutations occur in hotspots causing ...constitutive activation of the corresponding proteins. Thus, targeting RAS mutation in MM will increase therapeutic efficiency and potentially overcome drug resistance. We identified germinal center kinase (GCK) as a novel therapeutic target in MM with RAS mutation. GCK knockdown (KD) in MM cells demonstrated in vitro and in vivo that silencing of GCK induces MM cell growth inhibition, associated with blocked MKK4/7-JNK phosphorylation and impaired degradation of IKZF1/3, BCL-6, and c-MYC. These effects were rescued by overexpression of a short hairpin RNA (shRNA)-resistant GCK, thereby excluding the potential off-target effects of GCK KD. In contrast, overexpression of shRNA-resistant GCK kinase-dead mutant (K45A) inhibited MM cell proliferation and failed to rescue the effects of GCK KD on MM growth inhibition, indicating that GCK kinase activity is critical for regulating MM cell proliferation and survival. Importantly, the higher sensitivity to GCK KD in RASMut cells suggests that targeting GCK is effective in MM, which harbors RAS mutations. In accordance with the effects of GCK KD, the GCK inhibitor TL4-12 dose-dependently downregulated IKZF1 and BCL-6 and led to MM cell proliferation inhibition accompanied by induction of apoptosis. Here, our data identify GCK as a novel target in RASMut MM cells, providing a rationale to treat RAS mutations in MM. Furthermore, GCK inhibitors might represent an alternative therapy to overcome immunomodulatory drug resistance in MM.
•GCK activity is critical in MM harboring RAS mutations.•GCK inhibition induces degradation of IKZF1/3 in a Cereblon-independent fashion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast ...activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h
bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h
myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h
Rag2
results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.
Graft-vs-host disease (GVHD) is a donor T-cell-mediated disorder affecting the recipient's skin, gastrointestinal tract, lungs, and liver. It complicates up to 70% of hematopoietic cell ...transplantation and is associated with high morbidity and mortality rates.
An extensive review of the literature has been performed to include the most current consensus on the histopathologic diagnosis of gastrointestinal and liver GVHD.
In this review, we present an overview of GVHD, with emphasis on the histopathologic evaluation of gastrointestinal and liver specimens, including the most important differential diagnoses and possible pitfalls.
Histopathologic examination remains the mainstay of diagnosis of gastrointestinal and liver GVHD and is interpreted in conjunction with clinical and laboratory data.
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