Table of Contents
Nolte and Margadant review the current understanding of the activation and inactivation of integrin receptors expressed by hematopoietic cells and the role of these conformational changes in modulating platelet and leukocyte function.
CLINICAL TRIALS AND OBSERVATIONS
Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies
Clinical Trials & Observations
Relapse following chemeric antigen receptor (CAR) T-cell therapy can arise from progressive loss of the CAR T cells or from loss of the target antigen by tumor cells. Wang et al report that using a mix of CAR T cells targeting CD19 and CD22 reduces relapse with antigen-negative tumor cells. However, a lack of CAR T-cell persistence leads to increased relapse with antigen-positive cells.
IMMUNOBIOLOGY AND IMMUNOTHERAPY
T-cell activation leads to regulated increases in cytoplasmic calcium through inositol 1,4,5-triphosphate (IP3), a process balanced by phosphorylation and inactivation of IP3 by inositol 1,4,5-trisphosphate 3-kinase B (Itpkb). The investigators demonstrate that inhibition of Itpkb sustains increased intracellular Ca, leads to T-cell apoptosis, and inhibits graft-versus-host disease without impairing graft-versus-leukemia effects.
Li and colleagues report the genomic landscape of over 100 patients with relapsed acute lymphoblastic leukemia. Analysis of diagnosis-relapse-remission trios suggest that whereas early relapse is mediated by retained subclones, late relapse is driven by mutations induced by and conferring resistance to chemotherapy.
Transcription factors are important drivers in acute myeloid leukemia (AML), but they are notoriously difficult to target. The authors demonstrate that inhibition of salt-inducible kinase (SIK3) inhibits AML cell proliferation in cells dependent on the transcription factor MEF2C, identifying a small molecule that can disrupt a leukemogenic transcription factor pathway.
LETTERS TO BLOOD
Inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) controls activated T-cell calcium flux. Drug inhibitor and T-cell Itpkb deficiency selectively deleted graft-versus-host disease (GVHD) T cells. The image shows a murine chronic GVHD lung section with peribronchial collagen (blue) only present when Itpkb is functional. See the article by Thangavelu et al on page 28.
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