Immunoliposomes in Acute Myeloid Leukaemia Therapy: An Overview of Possible Targets and Obstacles

:Acute Myeloid Leukaemia (AML) is the neoplastic transformation of Hematopoietic Stem Cells (HSC) and relapsed disease is a major challenge in the treatment. Despite technological advances in the field of medicine and our heightened knowledge regarding the pathogenesis of AML, the initial therapy of “7+3” Cytarabine and Daunorubicin has remained mainly unchanged since 1973. AML is a disease of the elderly, and increased morbidity in this patient group does not allow the full use of the treatment and drug-resistant relapse is common.:Nanocarriers are drug-delivery systems that can be used to transport drugs to the bone marrow and target Leukemic Stem Cells (LSC), conferring less side-effects compared to the free-drug alternative. Nanocarriers also can be used to favour the transport of drugs that otherwise would not have been used clinically due to toxicity and poor efficacy. Liposomes are a type of nanocarrier that can be used as a dedicated drug delivery system, which can also have active ligands on the surface in order to interact with antigens on the target cells or tissues. In addition to using small molecules, it is possible to attach antibodies to the liposome surface, generating so-called immunoliposomes. By using immunoliposomes as a drug-delivery system, it is possible to minimize the toxic side effects caused by the chemotherapeutic drug on healthy organs, and at the same time direct the drugs towards the remaining AML blasts and stem cells.:This article aims to explore the possibilities of using immunoliposomes as a drug carrier in AML therapy. Emphasis will be on possible target molecules on the AML cells, leukaemic stem cells, as well as bone marrow constituents relevant to AML therapy. Further, some conditions and precautions that must be met for immunoliposomes to be used in AML therapy will be discussed.

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Vascular Niche E-Selectin Protects Acute Myeloid Leukaemia Stem Cells from Chemotherapy

Blood ◽

10.1182/blood.v124.21.620.620 ◽

2014 ◽

Vol 124 (21) ◽

pp. 620-620 ◽

Cited By ~ 15

Author(s):

Ingrid G Winkler ◽

Valerie Barbier ◽

Diwakar R Pattabiraman ◽

Thomas J Gonda ◽

John L. Magnani ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Small Molecule ◽

Adhesion Molecule ◽

High Dose ◽

Vascular Niche ◽

Vascular Adhesion ◽

Acute Myeloid

Abstract We recently reported that vascular adhesion molecule E-selectin is a key component of the bone marrow vascular niche, ‘awakening’ otherwise dormant Haematopoietic Stem Cells (HSC) (Winkler et al., Nat Med 2012). Following cytotoxic chemotherapy or radiation injury, E-selectin expression in the bone marrow increases ~10 to 20-fold during the recovery phase, at a time when HSC must cycle to replenish the blood and immune systems. When E-selectin is absent (in gene deleted mice) or E-selectin is therapeutically blocked using the small molecule glycomimetic antagonist GMI-1271, a greater proportion of HSC return to quiescence following radiation or chemotherapy. We now report cell surface E-selectin to be also upregulated 5 to 10-fold on the BM vasculature in mice with acute myeloid leukaemia (AML). This raises the interesting question: how do AML leukaemia stem cells (LSC) respond to E-selectin at the vascular niche? Using models of murine AML generated by retroviral transduction of the MLL-AF9 fusion oncogene into HSC, we found leukemic blasts rapidly upregulate E-selectin binding potential upon oncogenic transformation. In fact targeted disruption of these E-selectin-mediated interactions by administration of GMI-1271 injection distrupts adhesion and localization of AML cells and was sufficient to continually mobilise leukaemic blasts into the blood for at least 24 hours after a single injection at 40 mg/kg, suggesting that E-selectin-mediated interactions play a role in retaining LSC within BM niches. We next queried whether E-selectin-mediated signalling may help promote LSC survival following therapy. To test this, cohorts of 20 wildtype or 20 E-selectin knock-out mice were transplanted with the same AML cells, then 4 weeks later, half were treated with high dose cytarabine (2 x 900mg/kg at 12hour interval) while the other half remained untreated. At 24 hours after the first cytarabine injection, BM cells were harvested to measure numbers of surviving functional LSC by limiting-dilution transplantation assays in irradiated wild-type syngenic recipients and the proportion of these recipients that developed leukemia was used to calculate the original number of surviving LSC by Poisson’s distribution. We found that although the absence of E-selectin had no effect on total LSC numbers per femur, the absence of E-selectin dramatically increased sensitivity of LSC to cytarabine treatment (20-fold). These results indeed suggest that E-selectin is a key vascular niche component mediating LSC chemoresistance. Our data are also consistent with previous xenograft models in immune-deficient mice showing that the few human CD34+ AML LSC that survived chemotherapy, were observed clustered around endosteal vascular endothelium in recipient mice (Ishikawa et al., Nat BioTechnol 2007; Ninomiya et al., Leukemia 2007) where E-selectin is expressed. In summary our data confirm that niche factors alone can strongly influence LSC sensitivity to chemotherapy, and suggest a chemoprotective role for the vascular adhesion molecule E-selectin which is upregulated in the bone marrow of leukaemic mice, Taken together, these data identify E-selectin as a novel therapeutic target for the treatment of AML leukemic stem cells in that in vivo inhibition by the small molecule glycomimetic E-selectin antagonist GMI-1271 may improve chemosensitivity. Disclosures Winkler: FibroGen Inc.: Research Funding. Magnani:GlycoMimetics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Development of anticancer drug delivery system based on bone marrow-derived multipotent mesenchymal stem cells

Journal of Physics Conference Series ◽

10.1088/1742-6596/1461/1/012128 ◽

2020 ◽

Vol 1461 ◽

pp. 012128

Author(s):

Oleksii O Peltek ◽

Albert R Muslimov ◽

Mikhail V Zyuzin ◽

Timofey E Karpov ◽

Alexander S Timin

Keyword(s):

Drug Delivery ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Drug Delivery System ◽

Anticancer Drug ◽

Delivery System ◽

Anticancer Drug Delivery ◽

Multipotent Mesenchymal Stem Cells

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CD34+CD38-CD123+ Cells Are Present in Virtually All Acute Myeloid Leukaemia Blasts: A Promising Single Unique Phenotype for Minimal Residual Disease Detection

Acta Haematologica ◽

10.1159/000480448 ◽

2017 ◽

Vol 138 (3) ◽

pp. 175-181 ◽

Cited By ~ 9

Author(s):

Adhra Al-Mawali ◽

Avinash Daniel Pinto ◽

Shoaib Al-Zadjali

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Minimal Residual Disease ◽

De Novo ◽

Residual Disease ◽

Intention To Treat ◽

Minimal Residual ◽

Acute Myeloid

Background/Aims: In CD34-positive acute myeloid leukaemia (AML), the leukaemia-initiating event likely takes place in the CD34+CD38- cell compartment. CD123 has been shown to be a unique marker of leukaemic stem cells within the CD34+CD38- compartment. The aim of this study was to identify the percentage of CD34+CD38-CD123+ cells in AML blasts, AML CD34+CD38- stem cells, and normal and regenerating bone marrow CD34+CD38- stem cells from non-myeloid malignancies. Methods: Thirty-eight adult de novo AML patients with intention to treat were enrolled after the application of inclusion criteria from February 2012 to February 2017. The percentage of the CD34+CD38-CD123+ phenotype in the blast population at diagnosis was determined using a CD45-gating strategy and CD34+ backgating by flow cytometry. We studied the CD34+CD38-CD123+ fraction in AML blasts at diagnosis, and its utility as a unique phenotype for minimal residual disease (MRD) of AML patients. Results: CD123+ cells were present in 97% of AML blasts in patients at diagnosis (median 90%; range 21-99%). CD123+ cells were also present in 97% of the CD34+CD38- compartment (median 0.8164%, range 0.0262-39.7%). Interestingly, CD123 was not present in normal and regenerating CD34+CD38- bone marrow stem cells (range 0.002- 0.067 and 0.004-0.086, respectively). Conclusion: The CD34+CD38-CD123+ phenotype is present in virtually all AML blasts and it may be used as a unique single phenotype for MRD detection in AML patients.

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Paediatric malignancies

10.1093/med/9780199235636.003.0015 ◽

2011 ◽

Author(s):

Thankamma Ajithkumar ◽

Ann Barrett ◽

Helen Hatcher ◽

Natalie Cook

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Chronic Myeloid Leukaemia ◽

Acute Myeloid Leukaemia ◽

Acute Lymphoblastic Leukaemia ◽

Myeloid Leukaemia ◽

Lymphoblastic Leukaemia ◽

Bone Marrow Failure ◽

Clonal Proliferation ◽

Acute Myeloid

Leukaemia is the commonest cancer (accounting for >40% of cases) in children. It is a clonal proliferation of stem cells which leads to bone marrow failure and tissue infiltration.• Acute lymphoblastic leukaemia (ALL): 4/100,000• Acute myeloid leukaemia (AML): 0.7/100,000• Chronic myeloid leukaemia (CML): 0.2/100,000...

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