7 research outputs found
Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression
No full textAbstract not availableCraig T. Wallington-Beddoe, Jason A. Powell, Daochen Tong, Stuart M. Pitson, Kenneth F. Bradstock and Linda J. Bendal
Sphingosine kinase 2 supports the development of BCR/ABL-independent acute lymphoblastic leukemia in mice
No full textSphingosine kinase (SphK) 2 has been implicated in the development of a range of cancers and inhibitors of this enzyme are currently in clinical trial. We have previously demonstrated a role for SphK2 in the development of acute lymphoblastic leukemia (ALL).In this and our previous study we use mouse models: in the previous study the disease was driven by the proto-oncogene BCR/ABL1, while in this study cancer risk was elevated by deletion of the tumor suppressor ARF.Mice lacking ARF and SphK2 had a significantly reduced incidence of ALL compared mice with wild type SphK2.These results show that the role of SphK2 in ALL development is not limited to BCR/ABL1 driven disease extending the potential use of inhibitors of this enzyme to ALL patients whose disease have driver mutations other than BCR/ABL1.Vicki Xie, Daochen Tong, Craig T. Wallington-Beddoe, Ken F. Bradstock and Linda J. Bendal
Identification of sphingosine kinase 1 as a therapeutic target in B-lineage acute lymphoblastic leukaemia
No full textLink to a related website: https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bjh.15097, Open Access via UnpaywallAbstract not availableCraig T. Wallington‐Beddoe, Vicki Xie, Daochen Tong, Jason A. Powell, Alexander C. Lewis, Lorena Davies, Stuart M. Pitson, Kenneth F. Bradstock
Linda J. Bendal
Developing Chimeric Antigen Receptor T cells for the Treatment of Acute Myeloid Leukaemia
No full textAML is the most common acute leukaemia in adults with a high incidence of relapse following allogeneic HSCT. CAR T cells have shown remarkable outcomes in R/R B-cell leukaemia/lymphoma and MM. However, replicating this success in AML has been challenging chiefly due to heterogeneity of AML and lineage specific antigen expression in AML within and between patients, leading to immune escape and treatment failure.
CD123 is a leading target as it is frequently overexpressed in bulk and LSCs, with relatively lower expression on myeloid cells. Others in our lab have shown that PiggyBac CAR T cells targeting CD123 with natural ligand IL-3 recognition domain are effective in vitro. However, the discovery of CAR T derived lymphomas in treated patients prompted us to seek alternative gene modification systems. In this thesis, I explored 2 main themes, namely (i) to improve the genetic safety of CARIL3 therapy; and (ii) to increase the efficacy of anti-AML CAR T therapy.
Chapter 3 describes the pre-clinical development of CARIL3 using alternative lentiviral and PiggyBat systems with a focus on maintaining efficacy while exploring differences in gene integration patterns.
Chapter 4 looks at TIM-3 as another potential target with the aim of combining with CARIL3 to reduce the risk of antigen escape. The issue of fratricide due to expression of TIM-3 on T cells was overcome by CRISPR/Cas9 KO.
Chapter 5 explores whether the TIM-3 knockout could also improve efficacy of CARIL3, since TIM-3 is studied as a T cell exhaustion marker. The theme of genetic safety is again explored, by using CRISPR-Cas9 directed knock-in into the TIM-3 locus to minimise the risk of random integration.
While further work is required to enable safe and efficacious CAR T cells against AML in the clinic, the work in this thesis presents several proof-of-concept strategies taking significant steps towards realising this goal
Identification of sphingosine kinase 1 as a therapeutic target in B-lineage acute lymphoblastic leukaemia
No full textVariable CD34+ recovery of cryopreserved allogeneic HPC products: transplant implications during the COVID-19 pandemic.
No full textDonor registries and transplantation societies recommend cryopreservation of unrelated donor hemopoietic progenitor cell (HPC) products before the recipient commences conditioning therapy to mitigate the donor and travel risks associated with the COVID-19 pandemic. However, little is known regarding the postthaw quality of such allogeneic products or the effect of precryopreservation storage and processing on these characteristics. We investigated the postthaw CD34+ cell recovery and viability of 305 allogeneic HPC products cryopreserved at 9 laboratories across Australia. Median postthaw CD34+ cell recovery was 76% and ranged from 6% to 122%. Longer transit time before cryopreservation, white cell count (WCC) during storage, and complex product manipulation before cryopreservation were independently associated with inferior postthaw CD34+ cell recovery. Longer precryopreservation transit time and WCC were also associated with inferior postthaw CD34+ cell viability. We conclude that although postthaw CD34+ cell recovery and viability of cryopreserved allogeneic HPC is generally acceptable, there is a significant risk of poor postthaw product quality, associated with prolonged storage time, higher WCC, and complex product manipulation precryopreservation. Awareness of expected postthaw recovery and practices that influence it will assist collection, processing, and transplant centers in optimizing outcomes for transplant recipients
