Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials.

Because tissues from all three germ layers contribute to the pharyngeal arches, it is not surprising that all major signaling pathways are involved in their development. We focus on the role of retinoic acid (RA) signaling because it has been recognized for quite some time that alterations in this pathway lead to craniofacial malformations. Several studies exist that describe phenotypes observed upon RA perturbations in pharyngeal arch development; however, these studies did not address whether RA plays multiple roles at distinct time points during development. Here, we report the resulting phenotypes in the hindbrain, the neural crest–derived tissues, and the pharyngeal endoderm when RA synthesis is disrupted during zebrafish gastrulation and pharyngeal arch morphogenesis. Our results demonstrate that RA is required for the post‐gastrulation morphogenesis and segmentation of endodermal pouches, and that loss of RA does not affect the length of the pharyngeal ectoderm or medial endoderm along the anterior‐posterior axis. We also provide evidence that RA is not required for the specification of pharyngeal pouch endoderm and that the pharyngeal endoderm consists of at least two different cell populations, of which the pouch endoderm is sensitive to RA and the more medial pharyngeal endoderm is not. These results demonstrate that the developmental processes underlying pharyngeal arch defects differ depending on when RA signaling is disturbed during development. Developmental Dynamics 235:2695–2709, 2006.

Ionizing radiation and chemotherapy deplete hematopoietic stem cells and damage the vascular niche wherein hematopoietic stem cells reside. Hematopoietic stem cell regeneration requires signaling from an intact bone marrow (BM) vascular niche, but the mechanisms that control BM vascular niche regeneration are poorly understood. We report that BM vascular endothelial cells secrete semaphorin 3 A (SEMA3A) in response to myeloablation and SEMA3A induces p53 – mediated apoptosis in BM endothelial cells via signaling through its receptor, Neuropilin 1 (NRP1), and activation of cyclin dependent kinase 5. Endothelial cell – specific deletion ofNrp1orSema3aor administration of anti-NRP1 antibody suppresses BM endothelial cell apoptosis, accelerates BM vascular regeneration and concordantly drives hematopoietic reconstitution in irradiated mice. In response to NRP1 inhibition, BM endothelial cells increase expression and secretion of the Wnt signal amplifying protein, R spondin 2. Systemic administration of anti - R spondin 2 blocks HSC regeneration and hematopoietic reconstitution which otherwise occurrs in response to NRP1 inhibition. SEMA3A – NRP1 signaling promotes BM vascular regression following myelosuppression and therapeutic blockade of SEMA3A – NRP1 signaling in BM endothelial cells accelerates vascular and hematopoietic regeneration in vivo.

Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1⁺HK2⁺ cancers, HK1⁻HK2⁺ cancer subsets are sensitive to cytostasis induced by HK2^shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2^shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human multiple myeloma cell lines are HK1⁻HK2⁺. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human multiple myeloma cell cultures and human multiple myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in multiple myeloma cells in culture and prevented HK1⁻HK2⁺ multiple myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine multiple myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1⁻HK2⁺ multiple myeloma. Significance: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1⁻HK2⁺ multiple myeloma tumors. Graphical http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg. Graphical Abstract