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Article: Are the immuno-stimulatory properties of Lenalidomide extinguished by co-administration of Dexamethasone?

Hsu, Andy / Ritchie, David S / Neeson, Paul

2012 Volume 1, Issue 3, Page(s) 372–374

Abstract: Dexamethasone has been a mainstay of anti-myeloma therapy for 20 years. However, it is intensely immunosuppressive and may limit the efficacy of the immune system to control myeloma, and limit the exciting opportunities to use immune stimulating drug ... ...

Abstract	Dexamethasone has been a mainstay of anti-myeloma therapy for 20 years. However, it is intensely immunosuppressive and may limit the efficacy of the immune system to control myeloma, and limit the exciting opportunities to use immune stimulating drug therapies such as Lenalidomide to maximize the fight against this disease.
Language	English
Publishing date	2012-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.4161/onci.18963
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Myeloma natural killer cells are exhausted and have impaired regulation of activation.

D'Souza, Criselle / Keam, Simon P / Yeang, Han Xian Aw / Neeson, Michael / Richardson, Kelden / Hsu, Andy K / Canfield, Rachael / Bezman, Natalie / Robbins, Michael / Quach, Hang / Ritchie, David S / Harrison, Simon J / Trapani, Joseph A / Prince, H Miles / Beavis, Paul A / Darcy, Phillip K / Neeson, Paul J

Haematologica

2021 Volume 106, Issue 9, Page(s) 2522–2526

MeSH term(s)	Cytotoxicity, Immunologic ; Flow Cytometry ; Humans ; Killer Cells, Natural ; Multiple Myeloma
Language	English
Publishing date	2021-09-01
Publishing country	Italy
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2020.277525
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Article ; Online: Functional outcomes in Hirschsprung disease: A single institution's 12-year experience.

Thakkar, Hemanshoo S / Bassett, Christopher / Hsu, Andy / Manuele, Riccardo / Kufeji, Dorothy / Richards, Catherine A / Agrawal, Meena / Keshtgar, Alireza S

Journal of pediatric surgery

2017 Volume 52, Issue 2, Page(s) 277–280

Abstract: Aims: Hirschsprung disease (HD) is a chronic condition associated with long-term morbidity. We assessed the short and long-term functional outcomes of operated patients in a single institution over a 12-year period.: Materials and methods: We ... ...

Abstract	Aims: Hirschsprung disease (HD) is a chronic condition associated with long-term morbidity. We assessed the short and long-term functional outcomes of operated patients in a single institution over a 12-year period. Materials and methods: We conducted a retrospective review of all children operated for HD between 2002 and 2014. Postoperative functional outcomes were assessed using the Rintala Bowel Function Score (BFS, 0-20, 20=best score). We assessed hospital admissions, complications including Hirschsprung associated enterocolitis (HAEC) and the need for further surgical procedures. Results: 72 (52 male) patients were studied, of whom, 6 (8%) had a positive family history, 5 (7%) had Trisomy 21 and 5 (7%) had total colonic HD. The median age at diagnosis was 6.5days (2 days-6.7 years) and median follow-up was 6years (1-12years). All patients except two underwent a Duhamel pull-through procedure. The median age at surgery was 4months (6days-90months). 37 (51%) procedures were performed single-stage and 7 (10%) were laparoscopically assisted. Our early complication rate was 15%; 11 (15%) patients were treated for HAEC and 43 (60%) did not require any further surgery. 12 (17%) underwent injection of botulinum toxin, 7 (10%) needed residual spur division and 4 (5%) required an unplanned, post pull-through enterostomy for obstructive defecation symptoms and HAEC. Two (3%) patients underwent an Antegrade Colonic Enema (ACE) stoma. The median BFS was 17 (5-20). There were two deaths both out of hospital. Conclusions: Long-term functional outcomes following Duhamel Pull-Through surgery are satisfactory although 40% of patients needed some form of further surgical intervention. The management of anal sphincter achalasia has improved with the use of botulinum toxin and we advocate aggressive and early management of this condition for symptoms of obstructive defecation and HAEC. Level of evidence: III.
MeSH term(s)	Anal Canal/physiopathology ; Child ; Child, Preschool ; Constipation/diagnosis ; Constipation/etiology ; Constipation/physiopathology ; Digestive System Surgical Procedures ; Female ; Follow-Up Studies ; Hirschsprung Disease/physiopathology ; Hirschsprung Disease/surgery ; Humans ; Infant ; Infant, Newborn ; Male ; Postoperative Complications/diagnosis ; Postoperative Complications/physiopathology ; Retrospective Studies ; Treatment Outcome
Language	English
Publishing date	2017-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	80165-3
ISSN	1531-5037 ; 0022-3468
ISSN (online)	1531-5037
ISSN	0022-3468
DOI	10.1016/j.jpedsurg.2016.11.023
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Article ; Online: CD34+ cord blood DC-induced antitumor lymphoid cells have efficacy in a murine xenograft model of human ALL.

Cullup, Hannah / Hsu, Andy K W / Kassianos, Andrew J / McDonald, Kylie / Radford, Kristen J / Rice, Alison M

Journal of immunotherapy (Hagerstown, Md. : 1997)

2011 Volume 34, Issue 4, Page(s) 362–371

Abstract: Acute lymphocytic leukemia (ALL) patients who relapse after transplantation have few therapeutic options. An immunotherapeutic approach that enhances the graft versus leukemia effect may improve their survival. We postulate that cytotoxic T lymphocytes ( ... ...

Abstract	Acute lymphocytic leukemia (ALL) patients who relapse after transplantation have few therapeutic options. An immunotherapeutic approach that enhances the graft versus leukemia effect may improve their survival. We postulate that cytotoxic T lymphocytes (CTLs) generated from total RNA loaded cord blood CD34+-derived dendritic cells can control the kinetics of leukemic growth in a nonobese diabetic/severe combined immunodeficient (NOD-SCID) mouse model of human ALL. CD34+-derived dendritic cells electroporated with total RNA from an ALL xenograft generate antileukemic CTL with specificity for the ALL xenograft while sparing autologous cord blood mononuclear cells. The CD3+ T-cell compartment of the CTL was dominated by CD4+ T cells, although CD8+ T cells accounted for an average of 30% of the CD3+ T cells present. Expansion of both CD4+ and CD8+ memory and terminal effector memory subsets from predominantly naive cells was evident. Natural killer (NK) cells accounted for an average of 13% of the final antitumor lymphoid cells produced. Blocking experiments confirmed that the CD8+ T-cell compartment was responsible for the antileukemic activity of the polyclonal CTL pool. Administration of antileukemic CTL to NOD-SCID mice bearing ALL xenograft cells was able to delay, but not prevent the growth of ALL in vivo. Coadministration of antigen-loaded antigen-presenting cells did not further improve upon the delay in ALL engraftment kinetics observed with CTL alone. The efficacy of adoptively transferred polyclonal CTL can be improved with coadministration of recombinant human interleukin-2. However, in NOD-SCID mice, the efficacy of these adoptively transferred cells is masked by interleukin-2 stimulation of murine NK cells, which facilitate killing of ALL cells. Our data highlights the role for NK cells in antileukemic responses posttransplant. Collectively, our results support the notion that ALL-specific adoptive immunotherapy could be used clinically and provide an alternative strategy for preventing and treating disease relapse posttransplant and that the success of this therapy is likely to be maximized if given in the setting of minimal residual disease.
MeSH term(s)	Animals ; Antigens, CD34/immunology ; Dendritic Cells/immunology ; Female ; Fetal Blood/cytology ; Humans ; Immunotherapy, Adoptive ; Interleukin-2/pharmacology ; Killer Cells, Natural/drug effects ; Killer Cells, Natural/immunology ; Kinetics ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Mice ; Mice, SCID ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy ; RNA/metabolism ; Survival Analysis ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/metabolism ; T-Lymphocytes, Cytotoxic/transplantation ; Transplantation, Heterologous
Chemical Substances	Antigens, CD34 ; Interleukin-2 ; RNA (63231-63-0)
Language	English
Publishing date	2011-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1064067-8
ISSN	1537-4513 ; 1053-8550 ; 1524-9557
ISSN (online)	1537-4513
ISSN	1053-8550 ; 1524-9557
DOI	10.1097/CJI.0b013e31821b7230
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Article: Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib.

Neeson, Paul J / Hsu, Andy K / Chen, Yin R / Halse, Heloise M / Loh, Joanna / Cordy, Reece / Fielding, Kate / Davis, Joanne / Noske, Josh / Davenport, Alex J / Lindqvist-Gigg, Camilla A / Humphreys, Robin / Tai, Tsin / Prince, H Miles / Trapani, Joseph A / Smyth, Mark J / Ritchie, David S

Oncoimmunology

2015 Volume 4, Issue 9, Page(s) e1038011

Abstract: There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose ...

Abstract	There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8
Language	English
Publishing date	2015-05-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2015.1038011
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Article ; Online: Early thymus and activation-regulated chemokine (TARC) reduction and response following panobinostat treatment in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant.

Harrison, Simon J / Hsu, Andy K / Neeson, Paul / Younes, Anas / Sureda, Anna / Engert, Andreas / Prince, H Miles / Li, Martha / Savage, Paula / Bugarini, Roberto / Williams, Denise / Squier, Margaret / Ritchie, David S

Leukemia & lymphoma

2013 Volume 55, Issue 5, Page(s) 1053–1060

Abstract: Abstract In a phase 2 trial of panobinostat in 129 patients with relapsed or refractory Hodgkin lymphoma, exploratory analyses of chemokines and cytokines were prospectively performed in 109 patients to determine their association with clinical outcomes. ...

Abstract	Abstract In a phase 2 trial of panobinostat in 129 patients with relapsed or refractory Hodgkin lymphoma, exploratory analyses of chemokines and cytokines were prospectively performed in 109 patients to determine their association with clinical outcomes. Patients were categorized into two groups (reductions > median and reductions ≤ median) based on percentage change from baseline of log10 transformed measurements. Thymus and activation-regulated chemokine (TARC) was most strongly associated with clinical outcome. Early reduction of TARC was observed in responding patients, with the greatest reduction at cycle 1, day 15 (C1D15). Of 93 patients with C1D15 samples, there were three complete and 25 partial responses. The group with TARC reductions > median at C1D15 had more responders (18 [39%] vs. 10 [21%]), longer progression-free survival (10.6 vs. 4.9 months), shorter time to response and longer overall survival than the group with reductions ≤ median. This study is registered at www.ClinicalTrials.gov , NCT00742027.
MeSH term(s)	Adolescent ; Adult ; Aged ; Antineoplastic Agents/therapeutic use ; Biomarkers/blood ; Chemokine CCL17/blood ; Combined Modality Therapy ; Female ; Hematopoietic Stem Cell Transplantation ; Hodgkin Disease/blood ; Hodgkin Disease/mortality ; Hodgkin Disease/pathology ; Hodgkin Disease/therapy ; Humans ; Hydroxamic Acids/therapeutic use ; Indoles/therapeutic use ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Panobinostat ; Time Factors ; Transforming Growth Factor beta/blood ; Transplantation, Autologous ; Treatment Outcome ; Tumor Burden ; Young Adult
Chemical Substances	Antineoplastic Agents ; Biomarkers ; Chemokine CCL17 ; Hydroxamic Acids ; Indoles ; Transforming Growth Factor beta ; Panobinostat (9647FM7Y3Z)
Language	English
Publishing date	2013-08-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.3109/10428194.2013.820287
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Zs.A 2997: Show issues

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Article: Some findings on relative price change variance and inflation rate uncertainty in the Canadian CPI

Chambers, Edward J / Hsu, Andy

Applied economics 19 ,3, S. 285-303

1987

Author's details	E. J. Chambers and Andy Hsu
Keywords	Index ; Preisniveau ; Inflation ; Kanada
Language	English
Publisher	Routledge
Publishing place	Abingdon
Document type	Article
ZDB-ID	280176-0 ; 1473581-7
ISSN	1466-4283 ; 0003-6846
ISSN (online)	1466-4283
ISSN	0003-6846
Database	ECONomics Information System

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Article: RNA loading of leukemic antigens into cord blood-derived dendritic cells for immunotherapy.

Hsu, Andy K W / Kerr, Beverley M / Jones, Kathryn L / Lock, Richard B / Hart, Derek N J / Rice, Alison M

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

2006 Volume 12, Issue 8, Page(s) 855–867

Abstract: The manipulation of dendritic cells (DCs) ex vivo to present tumor-associated antigens for the activation and expansion of tumor-specific cytotoxic T lymphocytes (CTLs) attempts to exploit these cells' pivotal role in immunity. However, significant ... ...

Abstract	The manipulation of dendritic cells (DCs) ex vivo to present tumor-associated antigens for the activation and expansion of tumor-specific cytotoxic T lymphocytes (CTLs) attempts to exploit these cells' pivotal role in immunity. However, significant improvements are needed if this approach is to have wider clinical application. We optimized a gene delivery protocol via electroporation for cord blood (CB) CD34(+) DCs using in vitro-transcribed (IVT) mRNA. We achieved > 90% transfection of DCs with IVT-enhanced green fluorescent protein mRNA with > 90% viability. Electroporation of IVT-mRNA up-regulated DC costimulatory molecules. DC processing and presentation of mRNA-encoded proteins, as major histocompatibility complex/peptide complexes, was established by CTL assays using transfected DCs as targets. Along with this, we also generated specific antileukemic CTLs using DCs electroporated with total RNA from the Nalm-6 leukemic cell line and an acute lymphocytic leukemia xenograft. This significant improvement in DC transfection represents an important step forward in the development of immunotherapy protocols for the treatment of malignancy.
MeSH term(s)	Animals ; Antigen Presentation/genetics ; Antigen Presentation/immunology ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/immunology ; Cell Line, Tumor ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Electroporation/methods ; Fetal Blood/cytology ; Fetal Blood/immunology ; Humans ; Immunotherapy/methods ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Mice ; Neoplasm Transplantation/methods ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/immunology ; Neoplasms, Experimental/therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy ; RNA, Neoplasm/genetics ; RNA, Neoplasm/immunology ; RNA, Neoplasm/isolation & purification ; T-Lymphocytes, Cytotoxic/cytology ; T-Lymphocytes, Cytotoxic/immunology ; Transplantation, Heterologous
Chemical Substances	Antigens, Neoplasm ; RNA, Neoplasm
Language	English
Publishing date	2006-08
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1474865-4
ISSN	1083-8791
ISSN	1083-8791
DOI	10.1016/j.bbmt.2006.05.004
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Zs.A 5082: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 462: Show issues

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Article ; Online: The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy.

Hsu, Andy K / Quach, Hang / Tai, Tsin / Prince, H Miles / Harrison, Simon J / Trapani, Joseph A / Smyth, Mark J / Neeson, Paul / Ritchie, David S

Blood

2010 Volume 117, Issue 5, Page(s) 1605–1613

Abstract: Lenalidomide combined with dexamethasone is an effective treatment for refractory/relapsed multiple myeloma (MM). Lenalidomide stimulates natural killer (NK) cells and enhances antitumor responses. We assessed NK cell number and function in 25 patients ... ...

Abstract	Lenalidomide combined with dexamethasone is an effective treatment for refractory/relapsed multiple myeloma (MM). Lenalidomide stimulates natural killer (NK) cells and enhances antitumor responses. We assessed NK cell number and function in 25 patients with MM participating in a clinical trial of lenalidomide and dexamethasone. NK cell numbers increased from a mean of 2.20 ± 0.05 × 10(5)/mL (baseline) to a mean of 3.90 ± 0.03 × 10(5)/mL (cycle 6; P = .05); however, in vitro NK-cell-mediated cytotoxicity decreased from 48.9% ± 6.8% to 27.6% ± 5.1% (P = .0028) and could not be rescued by lenalidomide retreatment. Lenalidomide increased normal donor NK-cell cytotoxicity in vitro from 38.5% to 53.3%, but this was completely abrogated by dexamethasone. Dexamethasone suppression of NK cell-mediated cytotoxicity was partially reversed by a 3-day washout, but these cells remained refractory to lenalidomide-induced enhanced function. Lymphocyte subset depletion experiments revealed that lenalidomide's enhancement of NK cell-mediated cytotoxicity was mediated by CD4(+) T-cell production of interleukin 2 and that dexamethasone acted by suppressing interleukin-2 production. Similarly, the reduced ability of NK cells from patients with MM to respond to lenalidomide was also due to impaired CD4 T-cell function. Our findings indicate that lenalidomide immunostimulatory effects on patient NK cells are severely blunted by concurrent dexamethasone administration.
MeSH term(s)	Aged ; Anti-Inflammatory Agents/pharmacology ; Antigens, Differentiation, T-Lymphocyte/metabolism ; Antineoplastic Agents/pharmacology ; Blotting, Western ; Case-Control Studies ; Cell Proliferation/drug effects ; Clinical Trials, Phase II as Topic ; Cytotoxicity, Immunologic ; Dexamethasone/pharmacology ; Drug Resistance, Neoplasm ; Drug Therapy, Combination ; Flow Cytometry ; Humans ; Immunization ; Interleukin-2/metabolism ; Killer Cells, Natural/physiology ; Lenalidomide ; Lymphocyte Activation/drug effects ; Multiple Myeloma/drug therapy ; Multiple Myeloma/pathology ; NK Cell Lectin-Like Receptor Subfamily K/metabolism ; Natural Cytotoxicity Triggering Receptor 1/metabolism ; Prospective Studies ; T-Lymphocytes/drug effects ; Thalidomide/analogs & derivatives ; Thalidomide/pharmacology
Chemical Substances	Anti-Inflammatory Agents ; Antigens, Differentiation, T-Lymphocyte ; Antineoplastic Agents ; CD226 antigen ; Interleukin-2 ; KLRK1 protein, human ; NCR1 protein, human ; NK Cell Lectin-Like Receptor Subfamily K ; Natural Cytotoxicity Triggering Receptor 1 ; Thalidomide (4Z8R6ORS6L) ; Dexamethasone (7S5I7G3JQL) ; Lenalidomide (F0P408N6V4)
Language	English
Publishing date	2010-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2010-04-278432
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The drug vehicle and solvent N-methylpyrrolidone is an immunomodulator and antimyeloma compound.

Cell reports

2014 Volume 7, Issue 4, Page(s) 1009–1019

Abstract: N-methyl-2-pyrrolidone (NMP) is a common solvent and drug vehicle. We discovered unexpected antineoplastic and immunomodulatory activity of NMP in a cMYC-driven myeloma model. Coincident to this, NMP was identified as an acetyllysine mimetic and ... ...

Abstract	N-methyl-2-pyrrolidone (NMP) is a common solvent and drug vehicle. We discovered unexpected antineoplastic and immunomodulatory activity of NMP in a cMYC-driven myeloma model. Coincident to this, NMP was identified as an acetyllysine mimetic and candidate bromodomain ligand. Accordingly, NMP-treated cells demonstrated transcriptional overlap with BET-bromodomain inhibition, including downregulation of cMYC and IRF4. NMP's immunomodulatory activity occurred at sub-BET inhibitory concentrations, and, despite phenotypic similarities to lenalidomide, its antimyeloma activity was independent of the IMiD targets cereblon and Ikaros-1/3. Thus, low-affinity yet broad-spectrum bromodomain inhibition by NMP mediates biologically potent, cereblon-independent immunomodulation and at higher doses targets malignant cells directly via BET antagonism. These data reveal that NMP is a functional acetyllysine mimetic with pleotropic antimyeloma and immunomodulatory activities. Our studies highlight the potential therapeutic benefits of NMP, the consequences of current human NMP exposures, and the need for reassessment of scientific literature where NMP was used as an "inert" drug-delivery vehicle.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Cell Differentiation/drug effects ; Cells, Cultured ; Humans ; Immunologic Factors/pharmacology ; Mice ; Mice, Inbred C57BL ; Multiple Myeloma/drug therapy ; Multiple Myeloma/immunology ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Pyrrolidinones/pharmacology ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Immunologic Factors ; Pyrrolidinones ; N-methylpyrrolidone (JR9CE63FPM)
Language	English
Publishing date	2014-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2014.04.008
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