%0 Journal Article
%~ PubMed
%A Clancy, Leighton E
%A Blyth, Emily
%A Simms, Renee M
%A Micklethwaite, Kenneth P
%A Ma, Chun-Kei K
%A Burgess, Jane S
%A Antonenas, Vicki
%A Shaw, Peter J
%A Gottlieb, David J
%T Cytomegalovirus-specific cytotoxic T lymphocytes can be efficiently expanded from granulocyte colony-stimulating factor-mobilized hemopoietic progenitor cell products ex vivo and safely transferred to stem cell transplantation recipients to facilitate immune reconstitution.
%B Biology of Blood and Marrow Transplantation
%D 2013
%C United States
%I Elsevier Inc.
%V 19
%N 5
%P 725-734
%@ 1523-6536
%X 
%Z FOR Codes: 110202 110309


%0 Journal Article
%~ PubMed
%A Blyth, Emily
%A Clancy, Leighton
%A Simms, Renee
%A Ma, Chun K K
%A Burgess, Jane
%A Deo, Shivashni
%A Byth, Karen
%A Dubosq, Ming-Celine
%A Shaw, Peter J
%A Micklethwaite, Kenneth P
%A Gottlieb, David J
%T Donor-derived CMV specific T-cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation.
%B Blood
%D 2013
%C United States
%I American Society of Hematology
%V 121
%N 18
%P 3745-3758
%@ 0006-4971
%X 
%Z FOR Codes: 110202 110309


%0 Journal Article
%~ PubMed
%A Bilmon, Ian A
%A Kwan, John
%A Gottlieb, David
%A Kerridge, Ian
%A McGurgan, Mary
%A Huang, Gillian
%A George, Biju
%A Hertzberg, Mark
%A Bradstock, Kenneth F
%T Haploidentical bone marrow transplants for hematological malignancies using non-myeloablative conditioning therapy and post-transplant immunosuppression with cyclophosphamide: results from a single Australian centre.
%B Internal Medicine Journal
%D 2013
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 43
%N 2
%P 191-196
%@ 1445-5994
%X Background:??? HLA haploidentical bone marrow transplantation is a treatment option in patients with hematological malignancies who have no available HLA matched donor, but is limited by conditioning regimen toxicity, graft failure, relapse and graft versus host disease. Aims:??? To demonstrate safety and efficacy of haploidentical bone marrow transplantation with nonmyeloablative conditioning and high-dose post-transplant cyclophosphamide in adult patients with leukaemia or lymphoma. Methods:??? 12 patients, median age of 51 years, underwent transplantation with T cell replete bone marrow from a haplotype matched relative. The conditioning regimen consisted of cyclophosphamide, fludarabine, and low-dose TBI. Post-transplant immunosuppression consisted of a single dose of cyclophosphamide 50 mg/kg on day 3, followed by oral tacrolimus and mycophenolatemofetil. Outcomes reported are overall survival, engraftment and chimerism, toxicity, and clinical outcome. Results:??? All patients had neutrophil recovery (median 14.5 days), and 11 of 12 had platelet engraftment (median 17 days). Two patients had autologous reconstitution. Seven of 9 assessable patients had complete donor chimerism. Four patients had grade II-III GvHD, and none had grade IV GvHD. Four patientsdeveloped limited stage chronic GvHD. Five patients with AML relapsed. Two patients died of non-relapse causes, both from other malignancies, and 5 patients remain alive and relapse free. Median overall survival was324 days (range 88-1163). Conclusion:??? This regimen is feasible and well-tolerated in older patients with high risk leukemia or lymphoma, with minimal short-term toxicity, and low rates of GVHD. The proportion of disease-free survivors indicates a graft versus malignancy effect is present in survivors. ?? 2012 The Authors. Internal Medicine Journal ?? 2012 Royal Australasian College of Physicians.
%Z FOR Codes: 111206


%0 Journal Article
%~ PubMed
%A George, B
%A Kerridge, I H
%A Gilroy, N
%A Huang, G
%A Hertzberg, M S
%A Bradstock, K F
%A Gottlieb, D J
%T A risk score for early cytomegalovirus reactivation after allogeneic stem cell transplantation identifies low-, intermediate-, and high-risk groups: reactivation risk is increased by graft-versus-host disease only in the intermediate-risk group.
%B Transplant Infectious Disease
%D 2012
%C United States
%I Wiley-Blackwell Publishing, Inc.
%V 14
%N 2
%P 141-148
%@ 1399-3062
%X BACKGROUND: This retrospective study was aimed at establishing a clinical score to stratify the risk of cytomegalovirus (CMV) reactivation in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in order to direct strategies for post-transplant CMV monitoring and therapy. PATIENTS AND METHODS: In total, 335 adult patients undergoing HSCT were analyzed and divided into a training set (n = 235) and a validation set (n = 100). Logistic regression analysis on the training set identified recipient and donor CMV seropositivity, acute graft-versus-host disease (GVHD), and use of anti-thymocyte globulin or alemtuzumab as significant risk factors for CMV reactivation. Weighted scores were assigned to each factor. A weighted score (CMV scoring index [CSI]) was calculated for each patient using the scores of all risk factors except for GVHD. The index was collapsed into 3 risk groups - low risk (score of 0-2), intermediate risk (score of 3-5), and high risk (score of 6-7) - and reactivation rates were calculated. In the training set, CMV reactivation occurred in 5.8% in the low-risk group, 44.8% in the intermediate-risk group, and 67.7% in the high-risk group. RESULTS: In patients with an intermediate CSI only, significantly higher reactivation rates were seen in the presence of corticosteroid treatment for GVHD (57.8% vs. 24.5%, P < 0.01). These findings were similar in the validation set with reactivation rates of 0% in the low-risk, 46% in the intermediate-risk, and 68.4% in the high-risk groups. As seen in the training set, the presence of GVHD was associated with higher CMV reactivation rates only in the intermediate-risk group (64% vs. 28% in the absence of GVHD, P = 0.02). CONCLUSIONS: Identification of these 3 risk groups in association with the presence or absence of GVHD will help transplant units to make pre-transplant policy decisions about prophylactic, pre-emptive, or experimental CMV prevention strategies in groups of patients undergoing HSCT, as well as in those developing GVHD post transplant.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Blyth, Emily
%A Gaundar, Shivashni S
%A Clancy, Leighton
%A Simms, Renee M
%A Bilmon, Ian
%A Micklethwaite, Kenneth P
%A Gottlieb, David J
%T Clinical-grade varicella zoster virus-specific T cells produced for adoptive immunotherapy in hemopoietic stem cell transplant recipients.
%B Cytotherapy
%D 2012
%C United Kingdom
%I Informa Healthcare
%V 14
%N 6
%P 724-732
%@ 1477-2566
%X Background aims. Varicella zoster virus (VZV) causes life-long latent infection in healthy individuals, which reactivates in 10-68% of stem cell transplant patients. Reconstituting immunity through adoptive transfer of T cells specific for VZV may aid in the prophylaxis and treatment of VZV infections. The potential for generating T cells specific for VZV using a clinically approved VZV vaccine strain was investigated. Methods. The Varivax® vaccine was used to stimulate peripheral blood mononuclear cells from healthy donors. Only reagents approved for clinical manufacture were used. Monocyte-derived dendritic cells pulsed with Varivax (R) were used to stimulate autologous mononuclear cells at a responder to stimulator ratio of 10:1. On day 7, a second stimulation was performed; 20 U/mL interleukin (IL)-2 were added from day 7 and 50 U/mL IL-2 from day 14 onwards. Cell phenotype and functionality were assessed after 21 days of culture. Results. A mean increase of 11-fold in cell number was observed (n= 18). Cultures were mainly T cells (mean CD3 (+) 89.7%, CD4 (+) 54.2%, CD8 (+) 28.7%) with effector and central memory phenotypes. Cells produced one or more T helper (Th)1 cytokine (interferon-?, tumor necrosis factor-? and IL-2), and CD4 (+) (but not CD8 (+) ) cells expressed the cytoxicity marker CD107 when restimulated with VZV antigens. Conclusions. We have demonstrated a clinically applicable method that yields high numbers of highly reactive T cells specific for VZV. We propose that reconstructing host immunity through adoptive transfer of VZV-specific T cells will reduce the frequency of clinical VZV infection in the period of severe immune suppression that follows allogeneic stem cell transplantation.
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Gaundar, Shivashni S
%A Blyth, Emily
%A Clancy, Leighton
%A Simms, Renee M
%A Ma, Chun K K
%A Gottlieb, David J
%T In vitro generation of influenza-specific polyfunctional CD4(+) T cells suitable for adoptive immunotherapy.
%B Cytotherapy
%D 2012
%C United Kingdom
%I Informa Healthcare
%V 14
%N 2
%P 182-193
%@ 1477-2566
%X Abstract   Background aims. Influenza viruses cause potentially fatal respiratory infections in stem cell transplant patients. Specific T cells provide long-lived host adaptive immunity to influenza viruses, and the potential for generating such cells for clinical use was investigated. Methods. The inactivated influenza vaccine (Fluvax) approved for human use was used as the antigen source. Monocyte-derived dendritic cells pulsed with Fluvax were used to stimulate autologous peripheral blood mononuclear cells (PBMC) on days 0 and 7. Cells were expanded with interleukin (IL)-2 from day 7 onwards. Cell numbers and phenotype were assessed on day 21. The presence of influenza virus-specific cells was assessed by cytokine production and proliferative responses following restimulation with influenza antigens. Results. Over 21 days of culture, a mean fold increase of 26.3 in cell number was observed (n = 7). Cultures were predominantly effector and central memory CD4(+) cells, and expressed a phenotype characteristic of activated antigen-specific cells capable of B-cell helper function. Cytotoxic CD4(+) and CD8(+) cells specific for influenza and a high percentage of CD4(+) cells specific for each of three influenza viruses targeted by Fluvax (H1N1, H3N2 and Brisbane viruses) were generated. In addition, T cells expanded when restimulated with antigens derived from influenza viruses. Conclusions. We have demonstrated a clinically usable method for producing influenza virus-specific T cells that yield high numbers of highly reactive CD4(+) cells suitable for adoptive immunotherapy. We propose that reconstructing host immunity through adoptive transfer of influenza virus-specific T cells will reduce the frequency of influenza-related deaths in the period of severe immune suppression that follows stem cell transplantation.
%Z FOR Codes: 110309


%0 Journal Article
%~ PubMed
%A George, L
%A George, B
%A Gottlieb, D J
%A Hertzberg, M
%A Fernandez-Peñas, P
%T Lack of efficacy of rituximab in refractory sclerodermatous chronic GVHD.
%B Bone Marrow Transplantation
%D 2012
%C United Kingdom
%I Nature Publishing Group
%V 47
%N 5
%P 737-738
%@ 0268-3369
%X 
%Z FOR Codes: 110399


%0 Journal Article
%~ PubMed
%A Gaundar, Shivashni S
%A Clancy, Leighton
%A Blyth, Emily
%A Meyer, Wieland
%A Gottlieb, David J
%T Robust polyfunctional T-helper 1 responses to multiple fungal antigens from a cell population generated using an environmental strain of Aspergillus fumigatus.
%B Cytotherapy
%D 2012
%C United Kingdom
%I Elsevier Ltd
%V 14
%N 9
%P 1119-1130
%@ 1477-2566
%X 
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Jones, Kimberley
%A Nourse, Jamie P
%A Keane, Colm
%A Crooks, Pauline
%A Gottlieb, David
%A Ritchie, David S
%A Gill, Devinder
%A Gandhi, Maher K
%T Tumor-specific but not nonspecific cell-free circulating DNA can be used to monitor disease response in lymphoma.
%B American Journal of Hematology
%D 2012
%C United States
%I John Wiley & Sons, Inc.
%V 87
%N 3
%P 258-265
%@ 1096-8652
%X Recently, nontumor specific circulating DNA was shown to be elevated in a broad range of lymphomas, implicating a role as a potential biomarker. Epstein-Barr virus'' (EBV) presence within a proportion of lymphomas implies EBV-DNA has potential as a lymphoma-specific disease response biomarker. However, application would be restricted to EBV-associated lymphomas. Neither detailed comparison has been performed of lymphoma-specific versus nonspecific DNA as disease response biomarkers nor have the kinetics of circulating DNA during treatment been established, and the optimal methodology remains unknown. We prospectively evaluated DNA levels and clinical response of 63 lymphoma patients. DNA was measured in paired serum, plasma, and cell samples at five predetermined time-points taken prior, during and following treatment. Both cell-free (c-f) circulating EBV-DNA (in EBV-associated lymphoma) and nonspecific c-f DNA levels (in all lymphomas) were elevated and discriminatory at presentation compared to healthy controls. Nonspecific c-f DNA was significantly associated with baseline serum lactate dehydrogenase. Within EBV-associated lymphomas at presentation, there was a strong correlation between specific and nonspecific circulating c-f DNA (r = 0.9, P < 0.0001). However, only c-f EBV-DNA correlated with clinical/radiological response. In addition, c-f EBV-DNA, and not nonspecific c-f DNA, provided an early marker of relapsed and refractory disease. Serum versus plasma, and single versus multiple-copy EBV-gene targets were equivalent. Lymphoma-specific DNA is a disease response biomarker; however, nonspecific DNA reflected neither lymphoma-specific DNA nor therapeutic response. Lymphoma disease response can be monitored by blood tests, but new lymphoma-specific biomarkers need to be identified to broaden applicability.
%Z FOR Codes: 1102


%0 Journal Article
%~ PubMed
%A Suan, D
%A Booth, D R
%A Kennedy, I H
%A Downie, J
%A Earls, P
%A Gottlieb, D
%A Stewart, G J
%A Lin, M-W
%T Vitreal deposits in Val71Ala transthyretin amyloidosis.
%B Internal Medicine Journal
%D 2012
%C Australia, United Kingdom, Netherlands, United States
%I Wiley-Blackwell Publishing Asia
%V 42
%N 1
%P 106-108
%@ 1445-5994
%X 
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Blyth, Emily
%A Clancy, Leighton
%A Simms, Renee
%A Gaundar, Shivashni
%A O?connell, Philip
%A Micklethwaite, Kenneth
%A Gottlieb, David J
%T BK Virus-Specific T Cells for Use in Cellular Therapy Show Specificity to Multiple Antigens and Polyfunctional Cytokine Responses.
%B Transplantation
%D 2011
%C United States
%I Lippincott Williams & Wilkins
%V 92
%N 10
%P 1077-84
%@ 0041-1337
%X BK virus (BKV) infection causes hemorrhagic cystitis posthemopoietic stem-cell transplant and graft loss in renal transplant recipients. Reactivation occurs in up to 60% of patients in both groups. Treatment-related cellular immunosuppression is a major contributor to the development of BKV-related disease, but the targets of the immune response are not well characterized. Immunotherapy by adoptive transfer of cellular effectors has been shown to be effective in controlling and preventing some virus-related diseases in transplant recipients, particularly Epstein-Barr virus and cytomegalovirus. Infusion of BKV-specific T cells may potentially reconstitute functional BKV immunity and reduce clinical complications of BKV infection.
%Z FOR Codes: 110309


%0 Journal Article
%~ PubMed
%A Fromm, Phillip D
%A Gottlieb, David
%A Bradstock, Kenneth F
%A Hart, Derek N J
%T Cellular therapy to treat haematological and other malignancies: progress and pitfalls.
%B Pathology
%D 2011
%C United Kingdom, Australia
%I Informa Healthcare
%V 43
%N 6
%P 605-615
%@ 0031-3025
%X The recent Food and Drug Administration (FDA) approval of a cellular therapy to treat castration resistant prostate cancer has reinforced the potential of cellular therapy to consolidate current pharmacological approaches to treating cancer. The emergence of the cell manufacturing facility to facilitate clinical translation of these new methodologies allows greater access to these novel therapies. Here we review different strategies currently being explored to treat haematological malignancies with a focus on adoptive allogeneic or autologous transfer of antigen specific T cells, NK cells or dendritic cells. These approaches all aim to generate immunological responses against overexpressed tissue antigens, mismatched minor histocompatability antigens or tumour associated antigens. Current successes and limitations of these different approaches will be discussed with an emphasis on challenges encountered in generating long term engraftment, antigen selection and implementation as well as therapeutic immune monitoring of clinical responses, with examples from recent clinical trials.
%Z FOR Codes: 110316


%0 Journal Article
%~ PubMed
%A Herbert, K E
%A Levesque, J-P
%A Mills, A K
%A Gottlieb, D J
%A Cooney, J
%A Szer, J
%A Rasko, J
%A To, L B
%T How we mobilize haemopoietic stem cells.
%B Internal Medicine Journal
%D 2011
%C Australia, United Kingdom, Netherlands, United States
%I Wiley-Blackwell Publishing Asia
%V 41
%N 8
%P 588-594
%@ 1445-5994
%X Mobilization and collection of haemopoietic stem and progenitor cells (HSPC) is the cornerstone of autologous and allogeneic stem cell transplantation for a wide variety of haematological and some non-haematological malignancies. Centres providing this service face the challenge of optimizing the likelihood of successful collection of transplantable doses of cells, while maximizing the efficiency of the apheresis unit and minimizing the risk of toxicity as well as mobilization failure. Recent developments in the understanding of the molecular mechanisms of mobilization have led to the emergence of novel strategies for HSPC mobilization, which may assist in meeting these imperatives. The task for clinicians is how to incorporate the use of these strategies into practice, in the light of emerging evidence for efficacy and safety of these agents. Herein, the literature is reviewed, and a proposed algorithm for HSPC mobilization is presented.
%Z FOR Codes: 110399


%0 Journal Article
%~ PubMed
%A To, L Bik
%A Levesque, Jean-Pierre
%A Herbert, Kirsten E
%A Winkler, Ingrid G
%A Bendall, Linda J
%A Hiwase, Devendra K
%A Antonenas, Vicki
%A Rice, Alison M
%A Gottlieb, David
%A Mills, Anthony K
%A Rasko, John Ej
%A Larsen, Stephen
%A Beligaswatte, Ashanka
%A Nilsson, Susan K
%A Cooney, Julian P
%A Cambareri, Antony C
%A Lewis, Ian D
%T Mobilisation strategies for normal and malignant cells.
%B Pathology
%D 2011
%C United Kingdom, Australia
%I Wolters Kluwer UK Ltd.
%V 43
%N 6
%P 547-565
%@ 0031-3025
%X SUMMARY: This review evaluates the latest information on the mobilisation of haemopoietic stem cells for transplantation, with the focus on what is the current best practice and how new understanding of the bone marrow stem cell niche provides new insights into optimising mobilisation regimens. The review then looks at the mobilisation of mesenchymal stromal cells, immune cells as well as malignant cells and what clinical implications there are.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A George, Biju
%A Ferguson, Patricia
%A Kerridge, Ian
%A Gilroy, Nicole
%A Gottlieb, David
%A Hertzberg, Mark
%T The clinical impact of infection with Swine flu (H1N1 09) strain of influenza virus in hematopoietic stem cell transplant recipients.
%B Biology of Blood and Marrow Transplantation
%D 2011
%C United States
%I Elsevier Inc.
%V 17
%N 1
%P 147-153
%@ 1523-6536
%X There are limited data on the impact of H1N109 infection in patients undergoing hematopoietic stem cell transplantation (HSCT). We reviewed individual medical records of patients who underwent HSCT or were on follow-up post-HSCT between May and September 2009. Thirteen patients with H1N109 infection were identified: 2 <100 days post-HSCT, 7 >100 days post-HSCT, and 4 just prior to HSCT. Five (38.7%) had lower respiratory tract involvement (LRTI), whereas the remainder had upper respiratory tract involvement (URTI). LRTI occurred in patients who were profoundly neutropenic post-HSCT or on potent immunosuppression for chronic graft-versus-host disease (cGVHD). At 100 days post-H1N109 infection, only 1 patient with LRTI survived, whereas all with URTI are alive. Four patients successfully treated for H1N109 infection prior to HSCT underwent the procedure after 4 to 6 weeks without any complications. Another 6 patients received oseltamivir prophylaxis during conditioning and none developed H1N109 infection. In conclusion, H1N109 infection was associated with LRTI in HSCT recipients who were profoundly neutropenic or immunosuppressed. Prior H1N109 infection did not affect the successful outcome of HSCT and oseltamivir prophylaxis in a small group of recipients resulted in no infection. Further studies are required.
%Z FOR Codes: 110309 110323


%0 Journal Article
%~ PubMed
%A Prabhu, S
%A Gottlieb, D J
%A Varikatt, W
%A St Heaps, L
%A Diaz, S
%A Smith, A
%T Adult B-cell acute lymphoblastic leukemia with two unrelated abnormal cytogenetic clones.
%B Cancer Genetics and Cytogenetics
%D 2010
%C United States
%I Elsevier Inc.
%V 201
%N 1
%P 24-27
%@ 1873-4456
%X The presence of two different abnormal cell lines at diagnosis in hematologic malignancies is rare and raises the question of etiology and pathogenesis - two separate malignant lineages occurring together or a common stem cell malignancy? We present a 64-year-old woman who was evaluated for low platelet count and peripheral blasts. On the basis of the morphology, flow cytometry, and lack of myeloid-associated markers, a diagnosis of precursor B-cell acute lymphoblastic leukemia (B-ALL) was made. Cytogenetic analysis of the diagnostic bone marrow (BM) specimen revealed two unrelated abnormal clones - one had a dicentric (7;9)(p11;p11), resulting in the deletion of 7p and 9p, and the other had only trisomy 8. The dic(7;9) is a rare but recurrent abnormality in B-ALL, while trisomy 8 as a sole abnormality is most commonly associated with myeloid malignancies. After standard treatment for B-ALL, BM cytogenetic analysis showed disappearance of the dic(7;9) cell line but persistence of cells with trisomy 8. The presence of two unrelated clones suggestive of concomitant malignancies, possibly B-ALL with an underlying MDS, may have arisen by different mechanisms.
%Z FOR Codes: 111203


%0 Journal Article
%~ PubMed
%A George, B
%A Kerridge, I
%A Gilroy, N
%A Huang, G
%A Hertzberg, M
%A Gottlieb, D
%A Bradstock, K
%T Fludarabine-based reduced intensity conditioning transplants have a higher incidence of cytomegalovirus reactivation compared with myeloablative transplants.
%B Bone marrow transplantation
%D 2010
%C United Kingdom
%I Nature Publishing Group
%V 45
%N 5
%P 849-55
%@ 0268-3369
%X Two hundred and ten adult CMV seropositive patients undergoing myeloablative conditioning (MAC) [n=127] or reduced intensity conditioning (RIC) [n=83] transplants (HCT) were serially monitored for CMV reactivation and disease, using a qualitative polymerase chain reaction (PCR) followed by quantitation with pp65 antigen or quantitative PCR. CMV reactivation occurred in 53 RIC (63.9%) and 61 MAC (48%; P=0.03) transplants at a median of 47 days (range: 24-1977). Risk factors identified included acute GVHD (P=0.001), RIC regimen (P=0.03), unrelated donor (P=0.02), use of anti-thymocyte globulin/alemtuzumb (P=0.02) and use of bone marrow in MAC transplants (P=0.011). On multivariate analysis, RIC transplants and acute GVHD remained independent predictors. Treatment with antiviral drugs resulted in CMV negativity rates of 86.8% in MAC and 88.6% in RIC transplants. CMV disease occurred in 10.8% of RIC and 4.7% of MAC transplants (P=0.15). At a median follow-up of 26 months (range: 3-88), 48.1% of RIC and 50.3% of MAC transplants are alive. The higher incidence of CMV reactivation among RIC transplants suggests the need for novel prophylactic or pre-emptive strategies in this high-risk group of patients.
%Z FOR Codes: 1102 1112 1115


%0 Journal Article
%~ PubMed
%A George, B
%A Pati, N
%A Gilroy, N
%A Ratnamohan, M
%A Huang, G
%A Kerridge, I
%A Hertzberg, M
%A Gottlieb, D
%A Bradstock, K
%T Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy.
%B Transplant infectious disease : an official journal of the Transplantation Society
%D 2010
%C United States, Unit
%I Wiley-Blackwell Publishing, Inc.
%V 12
%N 4
%P 322-9
%@ 1399-3062
%X Between January 2001 and June 2008, 315 adult patients (median age 43 years, range 16-65) including 203 males and 112 females undergoing hematopoietic stem cell transplantation (HSCT) had serial monitoring for cytomegalovirus (CMV) followed by initiation of preemptive therapy. The majority (62.1%) had a conventional myeloablative transplant with 116 (36.9%) having a reduced-intensity conditioning (RIC) transplant, using either matched sibling/family (63.3%) or unrelated donors (36.7%). Graft source was peripheral blood stem cells in 257 (81.5%), bone marrow in 41 (13.1%), and cord blood in 16 (5.4%). T-cell depletion with anti-thymocyte globulin or alemtuzumab was used in 35%. Based upon CMV serostatus, patients were classified into low risk (donor [D]-/recipient [R]-), intermediate risk (D+/R-), or high risk (D-/R+ or D+/R+). Serial weekly monitoring for CMV viremia was performed using a qualitative polymerase chain reaction (PCR) and when positive, quantification was done using either pp65 antigen or a quantitative PCR. CMV reactivation was seen in 123 patients (39.1%) at a median of 50 days post HSCT (range 22-1978). CMV serostatus was the most important risk factor with incidence of 53% in the high-risk group (53.3%) compared with 10.2% in the intermediate risk and 0% in the low-risk group (P<0.0001). Other significant risk factors identified included use of alemtuzumab during conditioning (P=0.03), RIC transplants (P=0.06), and the presence of acute graft-versus-host disease (GVHD) (P<0.0001). On a multivariate analysis, CMV serostatus, RIC transplants, and acute GVHD remained independent predictors of CMV reactivation. All were treated with antiviral therapy with responses seen in 109 (88.6%). Sixteen patients (13%) developed CMV disease at a median of 59 days post HSCT (range 26 days-46 months), 8 of whom died. At a median follow up of 43 months (range 6-93), 166 patients (52.6%) are alive with a significantly higher survival among patients without CMV reactivation (57.2%) as compared with patients with CMV reactivation (45.5%; P=0.049). CMV reactivation and disease remains a major problem in high-risk patients undergoing allogeneic HSCT. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this specific group of patients.
%Z FOR Codes: 304


%0 Journal Article
%~ PubMed
%A Gottlieb, David J
%T T time for transplants.
%B Blood
%D 2010
%C United States
%I American Society of Hematology
%V 116
%N 22
%P 4391-4393
%@ 0006-4971
%X 
%Z FOR Codes: 110202 110323


%0 Journal Article
%~ PubMed
%A Micklethwaite, Kenneth P
%A Garvin, Frances M
%A Kariotis, Melina R
%A Yee, Leng L
%A Hansen, Anna M
%A Antonenas, Vicki
%A Sartor, Mary M
%A Turtle, Cameron J
%A Gottlieb, David J
%T Clinical-scale elutriation as a means of enriching antigen-presenting cells and manipulating alloreactivity.
%B Cytotherapy
%D 2009
%C United Kingdom
%I Informa Healthcare
%V 11
%N 2
%P 218-228
%@ 1477-2566
%X BACKGROUND AIMS: Clinical-scale elutriation using the Elutra(c) has been shown to enrich monocytes reliably for immunotherapy protocols. Until now, a detailed assessment of the four (F1-F4) non-monocyte fractions derived from this process has not been performed. METHODS: Using fluorescence-activated cell sorting (FACS), we performed phenotypic analyses to investigate the possible enrichment of T, B, natural killer (NK) and dendritic cells (DC) or their subsets in one or more Elutra fractions. RESULTS: Blood DC were enriched up to 10-fold in some fractions (F3 and F4) compared with the pre-elutriation apheresis product. This increased the number of DC that could be isolated from a given cell number by immunomagnetic separation. It was also found that CD62L(-) effector memory CD4(+) T cells were enriched in later fractions. In four of five cases tested, cells from F3 demonstrated decreased alloreactive proliferation in a mixed lymphocyte reaction compared with cells from the apheresis product. B cells were enriched in F1 compared with the apheresis product. CONCLUSIONS: In addition to providing enrichment of monocytes for the generation of DC, the Elutra enriches cell subsets that may be incorporated into and enhance existing immunotherapy and stem cell transplantation protocols.
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Kwan, Vu
%A Gottlieb, David
%T Endoscopic ultrasound-fine needle aspiration for the diagnosis of lymphoma: Are we there yet?
%B Journal of gastroenterology and hepatology
%D 2009
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 24
%N 12
%P 1808-1809
%@ 0815-9319
%X 
%Z FOR Codes: 1112


%0 Journal Article
%~ PubMed
%A Wallington-Beddoe, Craig T
%A Gottlieb, David J
%A Garvin, Fran
%A Antonenas, Vicki
%A Sartor, Mary M
%T Failure to achieve a threshold dose of CD34+CD110+ progenitor cells in the graft predicts delayed platelet engraftment after autologous stem cell transplantation for multiple myeloma.
%B Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
%D 2009
%C United States
%I Elsevier Inc.
%V 15
%N 11
%P 1386-1393
%@ 1523-6536
%X To predict platelet engraftment more accurately post autologous stem cell transplantation (SCT), we retrospectively analyzed the CD34(+)CD110(+) (CD110 or c-mpl, thrombopoietin receptor) content in the grafts of 70 patients undergoing transplantation for multiple myeloma (MM) with an in-house flow cytometric assay. We found that infusing at least 3.0 x 10(4) CD34(+)CD110(+) cells/kg clearly separated the cohort into those who achieved platelet engraftment before or after 21 days. This early megakaryocyte cell marker correlated more closely with early versus delayed platelet engraftment than CD34(+) measurements. Of the 70 patients, 4 required > or = 21 days to achieve platelet transfusion independence. Three of the 4 received a CD34(+)CD110(+) cell dose of <3.0 x 10(4) cells/kg, whereas 66 of 70 patients who received >3.0 x 10(4) CD34(+)CD110(+) cells/kg achieved platelet transfusion independence in <21 days (P < .001). Infusing >3.0 x 10(4) CD34(+)CD110(+) cells/kg was sensitive (100%) and specific (75%) for achieving platelet engraftment within 21 days. Patients with delayed platelet engraftment received a median of 2.28 x 10(4) CD34(+)CD110(+) cells/kg versus 12.1 x 10(4) cells/kg in those without this complication (P = .033). No effect was seen with neutrophil engraftment. Patients with early engraftment required a median of 1 platelet transfusion post transplant versus 2.5 in those with late engraftment (P = .009). A subthreshold absolute CD34(+)CD110(+) cell dose in the graft is a reliable predictor of delayed platelet engraftment, and could be used to guide the timing and number of peripheral blood stem cell (PBSC) collections for patients with MM undergoing an SCT.
%Z FOR Codes: 1107


%0 Journal Article
%~ PubMed
%A Brooke, Gary
%A Rossetti, Tony
%A Pelekanos, Rebecca
%A Ilic, Nina
%A Murray, Patricia
%A Hancock, Sonia
%A Antonenas, Vicki
%A Huang, Gillian
%A Gottlieb, David
%A Bradstock, Ken
%A Atkinson, Kerry
%T Manufacturing of human placenta-derived mesenchymal stem cells for clinical trials.
%B British journal of haematology
%D 2009
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 144
%N 4
%P 571-9
%@ 1365-2141
%X Mesenchymal stem cells (MSC) are being used increasingly in clinical trials for a range of regenerative and inflammatory diseases. Bone marrow is the traditional source but is relatively inaccessible in large volume. MSC have now been derived from tissues other than bone marrow including placenta and adipose tissue. We have used placenta obtained after delivery as a source of MSC and have been unable to detect any marked differences from marrow-derived MSC in terms of cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability. This report described our manufacturing process for isolating and expanding placenta-derived human MSC and their safe infusion into the first patient in a clinical trial program of human placenta-derived MSC.
%Z FOR Codes: 100404


%0 Journal Article
%~ PubMed
%A Bradstock, Kenneth
%A Hertzberg, Mark
%A Kerridge, Ian
%A Svennilson, Johan
%A George, Biju
%A McGurgan, Mary
%A Huang, Gillian
%A Antonenas, Vicki
%A Gottlieb, David
%T Single versus double unrelated umbilical cord blood units for allogeneic transplantation in adults with advanced hematological malignancies: a retrospective comparison of outcomes.
%B Internal medicine journal
%D 2009
%C Australia
%I Blackwell Publishing Asia
%V 39
%N 11
%P 744-51
%@ 1444-0903
%X Unrelated umbilical cord blood has emerged as an alternative stem cell source for allogeneic transplantation for patients with haematological malignancies, but in adults is limited by the low number of stem cells present in banked cord blood units. We report our experience with double cord blood transplants for adult patients. The aim of the study was to compare the outcomes of double unrelated cord blood transplants in adults with poor prognosis haematological diseases with single cord blood transplants.
%Z FOR Codes: 1102


%0 Journal Article
%~ PubMed
%A Cheung, Allen K L
%A Gottlieb, David J
%A Plachter, Bodo
%A Pepperl-Klindworth, Sandra
%A Avdic, Selmir
%A Cunningham, Anthony L
%A Abendroth, Allison
%A Slobedman, Barry
%T The role of the human cytomegalovirus UL111A gene in down-regulating CD4+ T-cell recognition of latently infected cells: implications for virus elimination during latency.
%B Blood
%D 2009
%C United States
%I American Society of Hematology
%V 114
%N 19
%P 4128-4137
%@ 0006-4971
%X The capacity of human cytomegalovirus (HCMV) to establish and maintain a latent infection from which it can later reactivate ensures its widespread distribution in the population, but the mechanisms enabling maintenance of latency in the face of a robust immune system are poorly understood. We examined the role of the HCMV UL111A gene, which encodes homologs of the immunosuppressive cytokine interleukin-10 in the context of latent infection of myeloid progenitor cells. A UL111A deletion virus was able to establish, maintain, and reactivate from experimental latency in a manner comparable with parental virus, but major histocompatibility complex class II levels increased significantly on the surfaces of cells infected with the deletion virus. Importantly, there was an increase in both allogeneic and autologous peripheral blood mononuclear cells and CD4(+) T-cell responses to UL111A deletion virus-infected myeloid progenitors, indicating that loss of the capacity to express viral interleukin-10 during latency results in latently infected cells becoming more readily recognizable by a critical arm of the immune response. The detection of a viral gene that suppresses CD4(+) T-cell recognition of latently infected cells identifies an immune evasion strategy that probably enhances the capacity of HCMV to persist in a latent state within the human host.
%Z FOR Codes: 110804


%0 Journal Article
%~ PubMed
%A George, B
%A Kerridge, I
%A Gottlieb, D
%A Huang, G
%A Hertzberg, M
%A Svennilson, J
%A Bradstock, K
%T A reduced intensity conditioning protocol associated with excellent survival in patients with myelofibrosis.
%B Bone marrow transplantation
%D 2008
%C United Kingdom
%I Nature Publishing Group
%V 42
%N 8
%P 567-8
%@ 0268-3369
%X 
%Z FOR Codes: 110323


%0 Journal Article
%~ PubMed
%A Micklethwaite, Kenneth P
%A Clancy, Leighton
%A Sandher, Upinder
%A Hansen, Anna M
%A Blyth, Emily
%A Antonenas, Vicki
%A Sartor, Mary M
%A Bradstock, Kenneth F
%A Gottlieb, David J
%T Prophylactic infusion of cytomegalovirus specific cytotoxic T-lymphocytes stimulated with Ad5f35pp65 gene modified dendritic cells following allogeneic haemopoietic stem cell transplantation.
%B Blood
%D 2008
%C United States
%I American Society of Hematology
%V 112
%N 10
%P 3974-81
%@ 1528-0020
%X Cytomegalovirus (CMV) and its therapy continue to contribute to morbidity and mortality in hemopoietic stem cell transplantation (HSCT). Many studies have demonstrated the feasibility of in vitro generation of CMV-specific T cells for adoptive immunotherapy of CMV. Few clinical trials have been performed showing the safety and efficacy of this approach in vivo. In this study, donor-derived, CMV-specific T cells were generated for 12 adult HSCT patients by stimulation with dendritic cells transduced with an adenoviral vector encoding the CMV-pp65 protein. Patients received a prophylactic infusion of T cells after day 28 after HSCT. There were no infusion related adverse events. CMV DNAemia was detected in 4 patients after infusion but was of low level. No patient required CMV-specific pharmacotherapy. Immune reconstitution to CMV was demonstrated by enzyme linked immunospot assay in all recipients with rapid increases in predominantly CMV-pp65 directed immunity in 5. Rates of graft-versus-host disease, infection, and death were not increased compared with expected. These results add to the growing evidence of the safety and efficacy of immunotherapy of CMV in HSCT, supporting its more widespread use. This study was registered at www.anzctr.org.au as #ACTRN12605000213640.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Goodwin, A
%A Gurney, H
%A Gottlieb, D
%T Allogeneic bone marrow transplant for refractory mediastinal germ cell tumour: possible evidence of graft-versus-tumour effect.
%B Internal medicine journal
%D 2007
%C Australia
%I Blackwell Publishing Asia
%V 37
%N 2
%P 127-129
%@ 1444-0903
%X Mediastinal germ cell tumours (GCT) carry a poor prognosis, particularly after relapse. We have reviewed the published reports of current treatments and describe a case with a cure after an allogeneic bone marrow transplant, which is not reported in the current published data. We believe that GCT may be susceptible to a graft-versus-tumour effect and suggest that patients with relapsed GCT be considered for allogeneic transplantation.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Micklethwaite, Kenneth
%A Hansen, Anna
%A Foster, Aaron
%A Snape, Elizabeth
%A Antonenas, Vicki
%A Sartor, Mary
%A Shaw, Peter
%A Bradstock, Ken
%A Gottlieb, David
%T Ex vivo expansion and prophylactic infusion of CMV-pp65 peptide-specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation.
%B Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
%D 2007
%C United States
%I Elsevier Inc.
%V 13
%N 6
%P 707-714
%@ 1083-8791
%X Cytomegalovirus reactivation and infection post-allogeneic hematopoietic stem cell transplant continue to cause morbidity and mortality. Current pharmacologic therapies are limited by side effects. Adoptive transfer of ex vivo generated cytomegalovirus-specific T cells has the potential to restore immunity, prevent cytomegalovirus, and circumvent the need for pharmacologic therapies. We have generated donor-derived cytomegalovirus-specific cytotoxic T cells using dendritic cells pulsed with the HLA-A2 restricted nonapeptide NLVPMVATV (NLV) derived from the cytomegalovirus-pp65 protein. These cytotoxic T cells have been given prophylactically to 9 recipients aged 4 to 65 years on or after day 28 post-allogeneic hematopoietic stem cell transplant. Only 2 of 9 recipients received T cell depletion in vivo or in vitro. There were no immediate adverse reactions to the infusions. During 97-798 days of follow-up, 2 recipients developed cytomegalovirus reactivation; neither developed cytomegalovirus disease or required pharmacotherapy. Three recipients developed acute graft versus host disease after infusion. Two recipients died, 1 from thrombotic thrombocytopenia purpura secondary to cyclosporine, 1 from complications of graft versus host disease. A transient increase in numbers of cytomegalovirus-specific T cells demonstrated by NLV-tetramer binding was seen in 6 recipients. Prophylactic adoptive transfer of NLV-specific T cells is safe and may be effective in preventing cytomegalovirus reactivation.
%Z FOR Codes: 110704 110708 110309


%0 Journal Article
%~ PubMed
%A Sartor, M M
%A Garvin, F
%A Antonenas, V
%A Bradstock, K F
%A Gottlieb, D J
%T Failure to achieve a threshold dose of CD34(+)CD110(+) progenitor cells in the graft predicts delayed platelet engraftment after autologous stem cell transplantation.
%B Bone marrow transplantation
%D 2007
%C UK
%I Nature Publishing Group
%V 40
%N 9
%P 851-7
%@ 0268-3369
%X In this study, we retrospectively analysed the utility of CD110 expression on CD34(+) cells as a predictor of delayed platelet transfusion independence in 39 patients who underwent autologous peripheral blood stem cell transplantation. Absolute CD34(+) cells and CD34(+) subsets expressing CD110 were enumerated using flow cytometry. Of the 39 patients, 7 required 21 days or more to achieve platelet transfusion independence. Six of the seven patients received a dose of CD34(+)CD110(+) cells below 6.0 x 10(4)/kg while 30 of 32 patients who achieved platelet transfusion independence in <21 days received a dose of CD34(+)CD110(+) cells >6.0 x 10(4)/kg (P<0.001). Patients with delayed platelet engraftment received a median dose of 5.2 x 10(4) CD34(+)CD110(+) cells/kg compared with a median dose of 16.4 x 10(4) cells/kg for those engrafting within 21 days (P=0.003). Further analysis showed that >6.0 x 10(4) CD34(+)CD110(+) cells/kg was highly sensitive (93.8%) and highly specific (85.7%) for achieving platelet transfusion independence within 21 days. Delay in platelet transfusion independence translated into an increased requirement for platelet transfusion (median 6 vs 2 transfusions, P<0.0001). The dose of CD34(+)/CD110(+) cells/kg infused at time of transplantation appears to be an important factor identifying patients at risk of delayed platelet engraftment.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Gottlieb, D J
%A Micklethwaite, K
%A Bradstock, K F
%A Li, Y-C H
%T Rapid expansion of tumor-reactive cells from HLA-matched siblings for adoptive immunotherapy of melanoma.
%B Cytotherapy
%D 2007
%C United Kingdom
%I Informa Healthcare
%V 9
%N 2
%P 133-143
%@ 1465-3249
%X BACKGROUND: Administration of expanded tumor-infiltrating lymphocytes in association with lymphodepleting chemotherapy is effective in some patients with advanced malignant melanoma. However, obtaining lymphocytes and subsequent expansion is labor intensive, making it impractical for broad clinical application. Allogeneic transplantation may have anti-melanoma efficacy because of a graft vs. tumor effect. The disappointing tumor control observed post-transplant suggests that adoptive immunotherapy using melanoma-reactive cells will be essential for sustained responses. METHODS: Melanoma cell lines were grown from two patients with advanced disease. High-level CD80 and CD86 expression was obtained in the tumor lines using a retroviral vector for gene transfer. Transduced melanoma and controls were cultured with mononuclear cells from HLA-identical sibling donors. RESULTS: Expression of CD80 and CD86, particularly the former, promoted marked expansion of lymphocytes from HLA-matched sibling donors. Proliferation of up to 300-fold after 4 weeks of culture was observed. Lymphocytes from cultures stimulated with CD80 demonstrated cytotoxicity against recipient-untransfected melanoma (45-75% specific lysis at an E:T ratio of 50:1). Although expanded lymphocytes were predominantly CD4(+), cytotoxicity was greatest in the numerically smaller CD8(+) subpopulation. Both CD4(+) and CD8(+) cells secreted IFN-gamma (but not IL-4) on exposure to untransduced stimulator melanoma cells. DISCUSSION: Our strategy generates a large number of melanoma-reactive lymphocytes from HLA-identical siblings using a 4-week culture strategy. Lymphocytes expanded in this way offer an alternative to tumor-infiltrating lymphocytes for allogeneic cellular immunotherapy after stem cell transplantation in young patients.
%Z FOR Codes: