ABSTRACT
Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective anti-leukemic effect post-HCT. We conducted a phase I clinical trial employing a novel TCR-T product targeting the minor H antigen HA-1 to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T post-HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8-co-receptor were successfully manufactured from HA-1 disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to nine HCT recipients who had developed disease recurrence post-HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, four patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with one ongoing at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial is registered at clinicaltrials.gov as NCT03326921.
ABSTRACT
Glutathione transferases (GST; EC 2.5.1.18) have been involved in many biotic and abiotic interactions of plants with their environment, but very little information is available on their regulation and possible role in drought tolerance. The GST8 gene of Arabidopsis thaliana encodes, as assessed by phylogenetic analysis, the homologue of an extremely conserved subgroup of Tau GSTs. During rapid dehydration of seedlings and progressive drought stress of mature plants, GST8 transcript levels increased following slower kinetics than RNAs for dehydration responsive genes RD29A and B, and strictly paralleled, in a mostly ABA independent manner, expression of oxidative stress marker PRX. GST8 RNA levels were also consistently increased by oxidative stress, high doses of auxin or cytokinin, and to a lesser extent, by wounding. RNA levels of ERD13, a previously described rapid dehydration responsive GST of the Phi class, were not co-regulated with those of GST8. Our results suggest that a drought-associated oxidative stress induces accumulation of GST8, whose function could be to counteract the effect of higher ROS production in stressed plants
ABSTRACT
Ten proteins differentially regulated by progressive drought stress in Arabidopsis Columbia wild-type, axr1-3 and axr2-1auxin-insensitive mutants, were identified from internal amino acid microsequencing. These proteins fell into two categories: (i) stress-related proteins, known to be induced by rapid water stress via abscisic acid (ABA)-dependent or -independent pathways [late embryogenesis abundant (LEA)-like and heat shock cognate (HS) 70, respectively], or in response to pathogens or oxidative stress [ß-1,3 glucanase (BG), annexin] and (ii) metabolic enzymes [glutamine synthetase (GS), fructokinase (Frk), caffeoyl-CoA-3-O-methyltransferase (CCoAOMT)]. The differential behaviour of these proteins highlighted a role for AXR2 and/or AXR1 in the regulation of their abundance during drought adaptation. In particular, reduced induction of RD29B, GS and annexin, and overexpression of BG2 were observed specifically in the axr1-3 mutant, which is dramatically affected in several ABA-dependent drought adaptive responses, such as drought rhizogenesis. Altogether these results indicate cross-talk between auxin- and ABA-signalling in Arabidopsis drought responses.
