Publications by authors named "Robert Weinkove"

39 Publications

An empirical test of the biodiversity hypothesis: Exposure to plant diversity is associated with a reduced risk of childhood acute lymphoblastic leukemia.

Sci Total Environ 2021 Jan 10;768:144627. Epub 2021 Jan 10.

Center for Public Health Research, Massey University-Wellington Campus, PO Box 756, Wellington 6140, New Zealand. Electronic address:

The biodiversity hypothesis posits that declining biodiversity may be responsible, at least in part, for the global increase in immune diseases. However, few studies have been able to demonstrate a link between exposure to biodiversity and specific health outcomes. We test whether exposure to plant diversity protects against childhood acute lymphoblastic leukemia (ALL) by promoting immune maturation. Our sample consisted of all children born in New Zealand from 1998 to 2013 (n = 899,126; 264 ALL cases), which we followed from birth to age five. We calculated plant-diversity metrics using the Global Biodiversity Information Facility, which contains over two million geocoded plant records in New Zealand. Consistent with previous research, children who had always lived in an urban area, or who had an older mother, were at greater risk for ALL, whereas children with older siblings were at lower risk. In addition, we found that plant-diversity metrics based on the maximum number of plant genera a child was exposed to during the first two years of life were protective of ALL. Specifically, exposure to the highest tertile of plant diversity was associated with a reduction in ALL risk of 35% (95% CI: 11%-53%). Exposure to plant diversity, and associated microbial communities, may be a viable public-health intervention to reduce the risk of ALL and possibly other immune diseases.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144627DOI Listing
January 2021

IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells.

Leukemia 2020 Nov 9. Epub 2020 Nov 9.

Key Laboratory of Regenerative Biology South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.

Chimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.
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http://dx.doi.org/10.1038/s41375-020-01085-1DOI Listing
November 2020

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial.

Lancet Oncol 2020 09;21(9):1188-1200

Department I of Internal Medicine and Center of Integrated Oncology Cologne Aachen Cologne Bonn Duesseldorf, German CLL Study Group, University Hospital, University of Cologne, Germany.

Background: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia.

Methods: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942.

Findings: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma).

Interpretation: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia.

Funding: F Hoffmann-La Roche and AbbVie.
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http://dx.doi.org/10.1016/S1470-2045(20)30443-5DOI Listing
September 2020

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.

Intern Med J 2020 06 15;50(6):667-679. Epub 2020 May 15.

Department of Haematology, St Vincent's Hospital, Sydney, New South Wales, Australia.

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.
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http://dx.doi.org/10.1111/imj.14859DOI Listing
June 2020

Managing haematology and oncology patients during the COVID-19 pandemic: interim consensus guidance.

Med J Aust 2020 06 13;212(10):481-489. Epub 2020 May 13.

Peter MacCallum Cancer Centre, Melbourne, VIC.

Introduction: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic.

Main Recommendations: During the COVID-19 pandemic: In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning.

Changes In Management As A Result Of This Statement: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence.

Endorsed By: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Children's Haematology/Oncology Group; Australia and New Zealand Society of Palliative Medicine; Australasian Society for Infectious Diseases; Bone Marrow Transplantation Society of Australia and New Zealand; Cancer Council Australia; Cancer Nurses Society of Australia; Cancer Society of New Zealand; Clinical Oncology Society of Australia; Haematology Society of Australia and New Zealand; National Centre for Infections in Cancer; New Zealand Cancer Control Agency; New Zealand Society for Oncology; and Palliative Care Australia.
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http://dx.doi.org/10.5694/mja2.50607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273031PMC
June 2020

B-cell prolymphocytic leukaemia with a t(4;14) FGFR3/IGH translocation: response to ibrutinib.

Pathology 2020 06 27;52(4):491-492. Epub 2020 Apr 27.

Wellington Blood and Cancer Centre, Capital and Coast District Health Board, Wellington, New Zealand; Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand; Department of Pathology and Molecular Medicine, University of Otago Wellington, Wellington, New Zealand. Electronic address:

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http://dx.doi.org/10.1016/j.pathol.2020.03.005DOI Listing
June 2020

Vaccines adjuvanted with an NKT cell agonist induce effective T-cell responses in models of CNS lymphoma.

Immunotherapy 2020 04 22;12(6):395-406. Epub 2020 Apr 22.

Malaghan Institute of Medical Research, P.O. Box 7060, Wellington 6242, New Zealand.

The efficacy of anti-lymphoma vaccines that exploit the cellular adjuvant properties of activated natural killer T (NKT) cells were examined in mouse models of CNS lymphoma. Vaccines were prepared by either loading the NKT cell agonist, α-galactosylceramide onto irradiated and heat-shocked B- and T-lymphoma cells, or chemically conjugating α-galactosylceramide to MHC-binding peptides from a lymphoma-associated antigen. Vaccine efficacy was analyzed in mice bearing intracranial tumors. Both forms of vaccine proved to be effective in preventing lymphoma engraftment through activity of T cells that accessed the CNS. Established lymphoma was harder to treat with responses constrained by Tregs, but this could be overcome by depleting Tregs prior to vaccination. Simply designed NKT cell-activating vaccines enhance T-cell responses and have the potential to protect against CNS lymphoma development or prevent CNS relapse. To be effective against established CNS lymphoma, vaccines need to be combined with Treg suppression.
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http://dx.doi.org/10.2217/imt-2019-0134DOI Listing
April 2020

Chimeric antigen receptor T-cell therapies: Optimising the dose.

Br J Clin Pharmacol 2020 09 24;86(9):1678-1689. Epub 2020 Mar 24.

Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand.

Lymphocytes such as T-cells can be genetically transduced to express a synthetic chimeric antigen receptor (CAR) that re-directs their cytotoxic activity against a tumour-expressed antigen of choice. Autologous (patient-derived) CAR T-cells have been licensed to treat certain relapsed and refractory B-cell malignancies, and numerous CAR T-cell products are in clinical development. As living gene-modified cells, CAR T-cells exhibit unique pharmacokinetics, typically proliferating within the recipient during the first 14 days after administration before contracting in number, and sometimes exhibiting long-term persistence. The relationship between CAR T-cell dose and exposure is highly variable, and may be influenced by CAR design, patient immune function at the time of T-cell harvest, phenotype of the CAR T-cell product, disease burden, lymphodepleting chemotherapy and subsequent immunomodulatory therapies. Recommended CAR T-cell doses are typically established for a specific product and indication, although for some products, stratification of dose based on disease burden may mitigate toxicity while maintaining efficacy. Re-evaluation of CAR T-cell dosing may be necessary following changes to the lymphodepleting regimen, for different disease indications, and following significant manufacturing changes, if product comparability cannot be demonstrated. Dose escalation trials have typically employed 3 + 3 designs, although this approach has limitations, and alternative phase I trial designs may facilitate the identification of CAR T-cell doses that strike an optimal balance of safety, efficacy and manufacturing feasibility.
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http://dx.doi.org/10.1111/bcp.14281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444796PMC
September 2020

Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE).

BMJ Open 2020 02 9;10(2):e034629. Epub 2020 Feb 9.

Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand

Introduction: Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL.

Methods And Analysis: Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×10 CAR T-cells/kg with a maximum dose of 1×10 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.

Ethics And Dissemination: Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.

Trial Registration Number: NCT04049513.
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http://dx.doi.org/10.1136/bmjopen-2019-034629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044946PMC
February 2020

Red cell transfusion in outpatients with myelodysplastic syndromes: a feasibility and exploratory randomised trial.

Br J Haematol 2020 04 20;189(2):279-290. Epub 2020 Jan 20.

Department of Haematology, Leeds Teaching Hospitals, Leeds, United Kingdom.

Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow-up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ-C30 and EQ-5D-5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85-100 g/l) with liberal thresholds (105 g/l, maintaining 110-125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention-to-treat population was 86% (95% confidence interval 75-94%) and 99% (95-100%) for restrictive and liberal arms respectively. Mean pre-transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient-centred outcomes.
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http://dx.doi.org/10.1111/bjh.16347DOI Listing
April 2020

Correction to: A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia.

J Hematol Oncol 2019 Nov 20;12(1):117. Epub 2019 Nov 20.

Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.

The original article [1] contains an error in authorship whereby author, Robert Weinkove's name is mistakenly inverted. The configuration noted in this Correction article should be considered instead along with author's updated affiliation.
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http://dx.doi.org/10.1186/s13045-019-0816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865043PMC
November 2019

Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.

N Engl J Med 2019 Jun 4;380(23):2225-2236. Epub 2019 Jun 4.

From Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne and University of Cologne (K.F., O.A.-S., J.B., A.-M.F., S. Robrecht, B.E., K.-A.K., M.H.), the Oncogeriatric Unit, Department of Geriatric Medicine, St. Marien Hospital (V.G.), CECAD (Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases) (M.H.), Center for Molecular Medicine Cologne (M.H.), Cologne, Department III of Internal Medicine, University Hospital Rostock, Rostock (S.B.), Department III of Internal Medicine, Ulm University, Ulm (E.T., S.S.), the Departments of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases, and Tropical Medicine, Klinikum Schwabing, Munich (C.-M.W.), Department II of Internal Medicine, Campus Kiel, University of Schleswig-Holstein, Kiel (M.R.), and the Department of Hematology, Oncology, and Rheumatology, Saarland University Medical School, Homburg (S.S.) - all in Germany; Roche Products, Welwyn Garden City, United Kingdom (M.T., M.D., S.W., K.H.); Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod, Russia (O.S.); the Division of Onco-Hematology, Santa Maria Terni Hospital, University of Perugia, Perugia, Italy (A.M.L.); the Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (J.P.-I.); the Haematology Department, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia (S.O.); First Internal Department, Multiprofile Hospital for Active Treatment Hristo Botev, Vratsa, Bulgaria (L.S.); the Hematology Department, Clinique Victor Hugo, Le Mans, France (K.L.D.); Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (L.M.F.); the Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen (C.U.N.); Wellington Blood and Cancer Centre, Capital and Coast District Health Board, and Malaghan Institute of Medical Research, Wellington, New Zealand (R.W.); Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada (S. Robinson); Moores Cancer Center, University of California San Diego, San Diego (T.J.K.), and Genentech, South San Francisco (M.M.) - both in California; AbbVie, North Chicago, IL (R.H.); and the Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, the Netherlands (A.W.L.).

Background: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known.

Methods: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated.

Results: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax-obinutuzumab group and 7.9% in the chlorambucil-obinutuzumab group. These differences were not significant.

Conclusions: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).
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http://dx.doi.org/10.1056/NEJMoa1815281DOI Listing
June 2019

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations.

Clin Transl Immunology 2019 11;8(5):e1049. Epub 2019 May 11.

Department of Microbiology and Immunology University of Otago Dunedin New Zealand.

Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4-1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti-CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile. The clinical impacts of combining costimulatory domains and of alternative costimulatory domains are not yet clearly established, and may be construct- and disease-specific. The aim of this review is to summarise the function and effect of established and emerging costimulatory domains and their combinations within CAR T cells.
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http://dx.doi.org/10.1002/cti2.1049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511336PMC
May 2019

A randomized controlled feasibility trial of paracetamol during febrile neutropenia in hemato-oncology patients.

Leuk Lymphoma 2019 06 18;60(6):1540-1547. Epub 2019 Jan 18.

f Medical Research Institute of New Zealand , Wellington , New Zealand.

The efficacy of paracetamol (acetaminophen) as an antipyretic during febrile neutropenia (FN) has not previously been established. We conducted a randomized double-blind placebo-controlled feasibility trial: hemato-oncology patients at high FN risk were randomly assigned to six hourly oral paracetamol (1 g) or placebo during the first 42 hours of FN. Fifty-three participants were screened, thirty-seven enrolled; 22 developed FN and commenced treatment (13 paracetamol; 9 placebo); recruitment rates were below, and retention rates met, pre-defined feasibility criteria. During the first 24 hours of FN, paracetamol recipients had significantly lower peak temperature than placebo: mean 38.2 (standard deviation 0.8) °C versus 38.9 (0.4) °C; difference -0.78 °C (95% CI -1.38 to -0.18);  = .013. Bacterial load measurement was not informative. Paracetamol lowers body temperature during FN, and definitive trials to determine its impact on FN outcomes are needed. Australian New Zealand Clinical Trials Registry reference ACTRN12613000601730; funded by Health Research Council of New Zealand.
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http://dx.doi.org/10.1080/10428194.2018.1538512DOI Listing
June 2019

Enhancing T cell responses and tumour immunity by vaccination with peptides conjugated to a weak NKT cell agonist.

Org Biomol Chem 2019 01;17(5):1225-1237

The Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.

Activated NKT cells can stimulate antigen-presenting cells leading to enhanced peptide antigen-specific immunity. However, administration of potent NKT cell agonists like α-galactosylceramide (α-GalCer) can be associated with release of high levels of cytokines, and in some situations, hepatotoxicity. Here we show that it is possible to provoke sufficient NKT cell activity to stimulate strong antigen-specific T cell responses without these unwanted effects. This was achieved by chemically conjugating antigenic peptides to α-galactosylphytosphingosine (α-GalPhs), an NKT cell agonist with very weak activity based on structural characterisation and biological assays. Conjugation improved delivery to antigen-presenting cells in vivo, while use of a cathepsin-sensitive linker to release the α-GalPhs and peptide within the same cell promoted strong T cell activation and therapeutic anti-tumour responses in mice. The conjugates activated human NKT cells and enhanced human T cell responses to a viral peptide in vitro. Accordingly, we have demonstrated a means to safely exploit the immunostimulatory properties of NKT cells to enhance T cell activation for virus- and tumour-specific immunity.
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http://dx.doi.org/10.1039/c8ob02982bDOI Listing
January 2019

Managing hypogammaglobulinaemia secondary to haematological malignancies in Australia and New Zealand: a clinician survey.

Intern Med J 2019 Mar;49(3):358-363

Department of Haematology, Monash Health, Melbourne, Victoria, Australia.

Background: Acquired hypogammaglobulinaemia secondary to haematological malignancies is associated with increased infection risk. Immunoglobulin (Ig) replacement reduces major infections but not mortality, and is costly. No prospective randomised trials have compared Ig replacement with prophylactic antibiotics.

Aims: To identify variation in current practice regarding management of secondary hypogammaglobulinaemia in Australia and New Zealand, to identify barriers to best practice, and to inform the development of a clinical trial assessing antibiotic prophylaxis in secondary hypogammaglobulinaemia.

Methods: We conducted an online survey of current clinical practice regarding management of secondary hypogammaglobulinaemia among haematologists in Australia and New Zealand.

Results: Seventy-two haematologists responded; 89% of whom reported commencing Ig replacement for secondary hypogammaglobulinaemia in the setting of recurrent or severe infection. Most monitored trough immunoglobulin G levels, most often 3 monthly. Criteria for stopping Ig replacement varied. Most respondents recommended influenza and pneumococcal vaccination, while only 21% reported using antibiotic prophylaxis. Few respondents (3%) reported prescribing prophylactic antibiotics before commencing Ig replacement. Most reported an interest in recruiting patients to a clinical trial comparing Ig replacement with prophylactic antibiotics.

Conclusion: In comparison to limited international data, this survey finds variation in practice, which may be due to differences in local policies governing access to Ig. These findings highlight the need for research into the indications for Ig commencement and cessation, and will inform design of prospective trials of infection prevention in secondary hypogammaglobulinaemia.
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http://dx.doi.org/10.1111/imj.14082DOI Listing
March 2019

A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia.

J Hematol Oncol 2018 02 20;11(1):25. Epub 2018 Feb 20.

Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.

Background: Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise in the treatment of B cell acute lymphocytic leukemia (B-ALL). However, its efficacy in B-ALL patients with extramedullary involvement is limited due to poor responses and neurotoxicity. Here, we utilized a third generation of CAR T cell vector, which contains the Toll/interleukin-1 receptor (ITR) domain of Toll-like receptor 2 (TLR2), to generate 1928zT2 T cells targeting CD19, and evaluated the efficacy of 1928zT2 T cells in relapse or refractory B-ALL patients with extramedullary involvement.

Methods: 1928zT2 T cells were generated by 19-28z-TLR2 lentiviral vector transfection into primary human T lymphocytes. The anti-leukemia effect of 1928zT2 T cells were determined by killing assays and in xenografts. Three patients diagnosed as relapse or refractory ALL with extramedullary involvement were infused with 1928zT2 T cells, and the clinical responses were evaluated by BM smear, B-ultrasonography, PET/CT, histology, flow cytometry, qPCR, ELISA, and luminex assay.

Results: 1928zT2 T cells exhibited enhanced effector function against CD19+ leukemic cells in vitro and in a xenograft model of human extramedullary leukemia. Notably, the 1928zT2 T cells eradicated extramedullary leukemia and induced complete remission in the three relapse and refractory ALL patients without serious adverse effects. 1928zT2 T cells expanded robustly in the circulation of these three patients and were detected in the cerebrospinal fluid of patient 3. These three patients experienced cytokine release syndrome (CRS) with grade 2 or 3, which remitted spontaneously or after tocilizumab treatment. None of the three patients suffered neurotoxicity or needed further intensive care.

Conclusions: Our results demonstrate that 1928zT2 T cells with TLR2 incorporation augment anti-leukemic effects, particularly for eradicating extramedullary leukemia cells, and suggest that the infusion of 1928zT2 T cells is an encouraging treatment for relapsed/refractory ALL patients with extramedullary involvement.

Trial Registration: ClinicalTrials.gov identifier NCT02822326 . Date of registration: July 4, 2016.
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http://dx.doi.org/10.1186/s13045-018-0572-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819207PMC
February 2018

A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients.

Cancer Immunol Immunother 2018 02 1;67(2):285-298. Epub 2017 Nov 1.

Malaghan Institute of Medical Research, PO Box 7060, Wellington, 6242, New Zealand.

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II-IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 10 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4 and CD8 T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.
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http://dx.doi.org/10.1007/s00262-017-2085-9DOI Listing
February 2018

Temporal changes in neutropenic blood culture isolates and disease associations: a single centre series of 1139 episodes.

Intern Med J 2017 Aug;47(8):962-965

Department of Pathology and Molecular Medicine, University of Otago, Wellington, New Zealand.

Neutropenic infections are life-threatening and require empiric antibiotic treatment. We examined 1139 blood culture isolates from our institution over a 36-year period from neutropenic patients to examine temporal trends and disease associations. Positive associations were found between viridans streptococci and acute myeloid leukaemia, coagulase negative staphylococci and acute lymphoblastic leukaemia and Pseudomonas aeruginosa and indolent B-cell malignancies.
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http://dx.doi.org/10.1111/imj.13509DOI Listing
August 2017

Red cell transfusion thresholds in myelodysplastic syndromes: a clinician survey to inform future clinical trials.

Intern Med J 2017 Jun;47(6):695-698

Supportive Care Disease Group, Australasian Leukaemia and Lymphoma Group, Melbourne, Victoria, Australia.

Optimal red cell transfusion thresholds in myelodysplastic syndrome are not established. In this survey of 110 Australasian haematologists' practice in myelodysplastic syndrome-related anaemia, 92% of respondents set transfusion thresholds, and would typically transfuse at a haemoglobin <80 g/L aiming for a post-transfusion haemoglobin 90-100 g/L, reflecting a restrictive transfusion strategy. Higher thresholds were typically used for patients with cardiovascular disease or anaemia symptoms. These results will inform the design of clinical trials comparing transfusion thresholds.
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http://dx.doi.org/10.1111/imj.13434DOI Listing
June 2017

Engaging Natural Killer T Cells as 'Universal Helpers' for Vaccination.

Drugs 2017 Jan;77(1):1-15

Malaghan Institute of Medical Research, PO Box 7060, Wellington, 6242, New Zealand.

Conventional vaccine adjuvants enhance peptide-specific T-cell and B-cell responses by modifying peptide stability or uptake or by binding to pattern-recognition receptors on antigen-presenting cells (APCs). This article discusses the application of a distinct mechanism of adjuvant activity: the activation of type I, or invariant, natural killer T (iNKT) cells to drive cellular and humoral immune responses. Using a semi-invariant T-cell receptor (TCR), iNKT cells recognize glycolipid antigens presented on cluster of differentiation (CD)-1d molecules. When their ligands are presented in concert with peptides, iNKT cells can provide T-cell help, 'licensing' APCs to augment peptide-specific T-cell and antibody responses. We discuss the potential benefits and limitations of exploiting iNKT cells as 'universal helpers' to enhance vaccine responses for the treatment and prevention of cancer and infectious diseases.
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http://dx.doi.org/10.1007/s40265-016-0675-zDOI Listing
January 2017

Immunity without innate lymphoid cells.

Nat Immunol 2016 10;17(11):1237-1238

Malaghan Institute of Medical Research, Wellington, New Zealand.

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http://dx.doi.org/10.1038/ni.3567DOI Listing
October 2016

Non-Invasive Detection of Anaemia Using Digital Photographs of the Conjunctiva.

PLoS One 2016 12;11(4):e0153286. Epub 2016 Apr 12.

Malaghan Institute of Medical Research, Wellington, New Zealand.

Background And Aims: Anaemia is a major health burden worldwide. Although the finding of conjunctival pallor on clinical examination is associated with anaemia, inter-observer variability is high, and definitive diagnosis of anaemia requires a blood sample. We aimed to detect anaemia by quantifying conjunctival pallor using digital photographs taken with a consumer camera and a popular smartphone. Our goal was to develop a non-invasive screening test for anaemia.

Patients And Methods: The conjunctivae of haemato-oncology in- and outpatients were photographed in ambient lighting using a digital camera (Panasonic DMC-LX5), and the internal rear-facing camera of a smartphone (Apple iPhone 5S) alongside an in-frame calibration card. Following image calibration, conjunctival erythema index (EI) was calculated and correlated with laboratory-measured haemoglobin concentration. Three clinicians independently evaluated each image for conjunctival pallor.

Results: Conjunctival EI was reproducible between images (average coefficient of variation 2.96%). EI of the palpebral conjunctiva correlated more strongly with haemoglobin concentration than that of the forniceal conjunctiva. Using the compact camera, palpebral conjunctival EI had a sensitivity of 93% and 57% and specificity of 78% and 83% for detection of anaemia (haemoglobin < 110 g/L) in training and internal validation sets, respectively. Similar results were found using the iPhone camera, though the EI cut-off value differed. Conjunctival EI analysis compared favourably with clinician assessment, with a higher positive likelihood ratio for prediction of anaemia.

Conclusions: Erythema index of the palpebral conjunctiva calculated from images taken with a compact camera or mobile phone correlates with haemoglobin and compares favourably to clinician assessment for prediction of anaemia. If confirmed in further series, this technique may be useful for the non-invasive screening for anaemia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153286PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829242PMC
August 2016

Innate-like T cell profile in myeloma: Severe deficiency of Vγ9Vδ2 T cells in aminobisphosphonate-treated patients.

Leuk Lymphoma 2016 9;57(4):977-80. Epub 2015 Oct 9.

b Wellington Blood and Cancer Centre, Capital and Coast District Health Board , Wellington , New Zealand .

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http://dx.doi.org/10.3109/10428194.2015.1088653DOI Listing
December 2016

NKT cell-dependent glycolipid-peptide vaccines with potent anti-tumour activity.

Chem Sci 2015 Sep 25;6(9):5120-5127. Epub 2015 Jun 25.

The Ferrier Research Institute , Victoria University of Wellington , PO Box 33436 , Lower Hutt 5046 , New Zealand . Email:

It is known that T cells can eliminate tumour cells through recognition of unique or aberrantly expressed antigens presented as peptide epitopes by major histocompatibility complex (MHC) molecules on the tumour cell surface. With recent advances in defining tumour-associated antigens, it should now be possible to devise therapeutic vaccines that expand specific populations of anti-tumour T cells. However there remains a need to develop simpler efficacious synthetic vaccines that possess clinical utility. We present here the synthesis and analysis of vaccines based on conjugation of MHC-binding peptide epitopes to α-galactosylceramide, a glycolipid presented by the nonpolymorphic antigen-presenting molecule CD1d to provoke the stimulatory activity of type I natural killer T (NKT) cells. The chemical design incorporates an enzymatically cleavable linker that effects controlled release of the active components . Chemical and biological analysis of different linkages with different enzymatic targets enabled selection of a synthetic vaccine construct with potent therapeutic anti-tumour activity in mice, and marked activity in human blood.
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http://dx.doi.org/10.1039/c4sc03599bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500832PMC
September 2015

An adjuvanted whole cell vaccine as post-remission immunotherapy for acute leukemia.

Oncoimmunology 2015 Apr 22;4(4):e995568. Epub 2015 Jan 22.

Malaghan Institute of Medical Research , Wellington, New Zealand ; School of Biological Sciences, Victoria University of Wellington , Wellington, New Zealand.

Many acute leukemia patients treated with chemotherapy are at high risk of relapse without allogeneic stem cell transplantation, an immunotherapy that is limited by significant toxicity and donor availability. We propose that post-remission vaccination with a simple autologous whole cell vaccine adjuvanted with α-galactosylceramide may be effective to prevent relapse of acute leukemia.
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http://dx.doi.org/10.1080/2162402X.2014.995568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485719PMC
April 2015

Association between early peak temperature and mortality in neutropenic sepsis.

Ann Hematol 2015 May 18;94(5):857-64. Epub 2014 Dec 18.

Wellington Blood & Cancer Centre, Capital & Coast District Health Board, Wellington, New Zealand,

Fever is often the first sign of neutropenic infection, but its prognostic impact has not been established. We aimed to determine whether early peak temperature is associated with mortality in patients with neutropenic sepsis admitted to intensive care units (ICUs). We used a database of admissions to 157 ICUs in Australia and New Zealand between 2005 and 2013 to seek an association between peak temperature within the first 24 h in ICU and in-hospital mortality in neutropenic and non-neutropenic sepsis. Odds ratios for in-hospital death were calculated for four temperature bands, adjusting for illness severity. Two patient cohorts were identified: neutropenic sepsis (N = 4027) and non-neutropenic sepsis (N = 114,040). In-hospital mortality was higher in neutropenic sepsis than non-neutropenic sepsis. In both cohorts, early peak temperature below 36.5 °C was associated with significantly increased mortality compared to normothermia. Among non-neutropenic patients, an early peak temperature of 37.5 °C or higher was associated with reduced mortality compared to normothermia. In contrast, in patients with neutropenic sepsis, fever was not associated with reduced mortality compared to normothermia. Similar findings were seen in a subgroup of the neutropenic sepsis cohort with a documented haematological malignancy. In neutropenic sepsis patients admitted to ICU, a temperature below 36.5 °C is associated with increased mortality compared with normothermia. In contrast to non-neutropenic sepsis, fever was not associated with a significant reduction in mortality in neutropenic patients. Interventional studies are needed to determine whether physical or pharmacological measures to reduce fever influence outcomes during neutropenic infections.
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http://dx.doi.org/10.1007/s00277-014-2273-zDOI Listing
May 2015

An autologous leukemia cell vaccine prevents murine acute leukemia relapse after cytarabine treatment.

Blood 2014 Nov 18;124(19):2953-63. Epub 2014 Sep 18.

Malaghan Institute of Medical Research, Wellington, New Zealand; School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand;

Acute leukemias with adverse prognostic features carry a high relapse rate without allogeneic stem cell transplantation (allo-SCT). Allo-SCT has a high morbidity and is precluded for many patients because of advanced age or comorbidities. Postremission therapies with reduced toxicities are urgently needed. The murine acute leukemia model C1498 was used to study the efficacy of an intravenously administered vaccine consisting of irradiated leukemia cells loaded with the natural killer T (NKT)-cell agonist α-galactosylceramide (α-GalCer). Prophylactically, the vaccine was highly effective at preventing leukemia development through the downstream activities of activated NKT cells, which were dependent on splenic langerin(+)CD8α(+) dendritic cells and which led to stimulation of antileukemia CD4(+) and CD8(+) T cells. However, hosts with established leukemia received no protective benefit from the vaccine, despite inducing NKT-cell activation. Established leukemia was associated with increases in regulatory T cells and myeloid-derived suppressor cells, and the leukemic cells themselves were highly suppressive in vitro. Although this suppressive environment impaired both effector arms of the immune response, CD4(+) T-cell responses were more severely affected. When cytarabine chemotherapy was administered prior to vaccination, all animals in remission posttherapy were protected against rechallenge with viable leukemia cells.
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http://dx.doi.org/10.1182/blood-2014-04-568956DOI Listing
November 2014