Omidubicel vs standard umbilical cord blood transplant, CAR T-cell associated lymphomas, and CD63 and ferritin export
In this week’s episode, we’ll review results of a phase 3 randomized study demonstrating shorter time to neutrophil and platelet recovery with an ex vivo expanded hematopoietic progenitor cell product called omidubicel as compared to standard umbilical cord transplantation. Next, we’ll look at preliminary data on the development of lymphomas originating from piggyBac-modified CD19 CAR T-cells, sounding a note of caution for researchers exploring new gene modification methodologies for CAR T-cell production. We’ll conclude with a report suggesting that the vesicular protein CD63 may orchestrate the transfer of iron-rich ferritin among cells.
Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study
Delayed engraftment and risk of graft failure have restricted the use of cord blood (CB) in allotransplantation. Horwitz et al report results of a phase 3 trial comparing use of a single CB unit expanded ex vivo for 21 days with nicotinamide in combination with stem cell factor, Flt3 ligand, interleukin-6, and thrombopoietin (omidubicel) with a standard unmanipulated single or double CB transplant. Omidubicel resulted in faster neutrophil engraftment (12 vs 22 days), platelet recovery, and B-cell and natural killer cell reconstitution than unmanipulated CB products, with lower incidence of viral and fungal infections and more time out of hospital.
Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells
Transposons present potential advantages over current retroviral transduction systems for the generation of gene-modified cellular therapy, including chimeric antigen receptor (CAR) T cells, but this technology is only just entering clinical trials. In a Plenary Paper, Micklethwaite and colleagues report the first clinical trial of piggyBac transposon–modified CAR T cells generated from HLA-matched sibling allogeneic donors. They report a high rate of complete remission in patients with refractory B-cell lymphomas postallograft, but also the first known cases of CAR T-cell lymphoma in 2 of 10 patients. These data have implications for the development of piggyBac transposon clinical gene transfer tools.
CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles
The interplay between intracellular and extracellular ferritin is not well understood despite the recognition 3 years ago that cellular ferritin can be exported into plasma by the exosome pathway. Yanatori et al report new insights into the triggers for ferritin secretion and how this is coordinated with iron metabolism. They demonstrate that CD63, a tetraspanin protein and constituent of extracellular vesicles, is induced by iron and in turn that this increases the secretion by various cells of CD63- positive extracellular vesicles containing iron-loaded ferritin.
Multimodal single-cell analysis of cutaneous T-cell lymphoma reveals distinct subclonal tissue-dependent signatures
Herrera et al used cutting-edge single-cell analyses to dissect the relationship between cutaneous and circulating cells in a small number of patients with Sézary syndrome. Their data on inferred copy number variation and transcriptomic signatures of malignant T cells suggest that Sézary syndrome cells emerge from the skin and colonize blood at different time points, generating intratumoral heterogeneity.
Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets
COVID-19 illness highlights the complex interplay of inflammation, immunity, hemostasis, and thrombosis. Bye et al show that immune complexes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and anti-spike immunoglobulin G (IgG) increase the formation of platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation of the Fc domain of the IgG is altered in a fashion recently identified in patients with severe COVID-19. These data may help explain the thromboinflammation in patients and point to new approaches to its prevention.
