East Melbourne, Australia
East Melbourne, Australia

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Ritchie D.S.,University of Melbourne | Ritchie D.S.,Hematology Immunology Translational Research Laboratory | Ritchie D.S.,Cancer Immunology Research Program | Ritchie D.S.,Peter MacCallum Cancer Center | And 37 more authors.
Molecular Therapy | Year: 2013

In a phase I study of autologous chimeric antigen receptor (CAR) anti-LeY T-cell therapy of acute myeloid leukemia (AML), we examined the safety and postinfusion persistence of adoptively transferred T cells. Following fludarabine-containing preconditioning, four patients received up to 1.3 × 109 total T cells, of which 14-38% expressed the CAR. Grade 3 or 4 toxicity was not observed. One patient achieved a cytogenetic remission whereas another with active leukemia had a reduction in peripheral blood (PB) blasts and a third showed a protracted remission. Using an aliquot of In111-labeled CAR T cells, we demonstrated trafficking to the bone marrow (BM) in those patients with the greatest clinical benefit. Furthermore, in a patient with leukemia cutis, CAR T cells infiltrated proven sites of disease. Serial PCR of PB and BM for the LeY transgene demonstrated that infused CAR T cells persisted for up to 10 months. Our study supports the feasibility and safety of CAR-T-cell therapy in high-risk AML, and demonstrates durable in vivo persistence. © The American Society of Gene and Cell Therapy.


Herbert K.E.,Peter MacCallum Cancer Center | Herbert K.E.,Center for Blood Cell Therapies | Herbert K.E.,University of Melbourne | Gambell P.,Peter MacCallum Cancer Center | And 17 more authors.
Bone Marrow Transplantation | Year: 2013

Haematopoietic stem and progenitor cells (HSPC) mobilization, using cytokine-Alone, is a well-tolerated regimen with predictable mobilization kinetics. Single-dose pegfilgrastim mobilizes HSPC efficiently; however, there is surprisingly little comparative data on its use without chemotherapy for HSPC mobilization. Pegfilgrastim-Alone and filgrastim-Alone mobilization regimens were compared in 52 patients with haematological malignancy. Pegfilgrastim 12 mg (n=20) or 6 mg (n=2) was administered Day 1 (D1) in 22 patients (lymphoma n=17; myeloma n=5). Thirty historical controls (lymphoma n=18; myeloma n=12) received filgrastim 10 mcg/kg daily from D1. Peripheral blood (PB) CD34+ counts reached threshold (≥5 × 106/L) and apheresis commenced on D4(4-5) and D4(4-6). Median PB CD34+ cell count on D1 of apheresis was similar (26.0 × 106/L (2.5-125.0 × 10 6/L) and 16.2 × 106/L (2.6-50.7 × 10 6/L); P=0.06), for pegfilgrastim and filgrastim groups, respectively. Target yield (≥2 × 106 per kg CD34+ cells) was collected in 20/22 (91%) pegfilgrastim patients and 24/30 (80%) in the filgrastim group (P=0.44), in a similar median number of aphereses (3(1-4) versus 3(2-6), respectively; P=0.85). A higher proportion of pegfilgrastim patients tended to yield ≥4 × 106 per kg CD34+ cells; 16/22 (73%) versus 14/30 (47%) filgrastim patients (P=0.09). One pegfilgrastim patient developed hyperleukocytosis that resolved without incident. Pegfilgrastim-Alone is a simple, well-tolerated, and attractive option for outpatient-based HSPC mobilization with similar mobilization kinetics and efficacy to regular filgrastim. © 2013 Macmillan Publishers Limited. All rights reserved.


Gowans E.J.,Burnet Institute | Gowans E.J.,Womens and Childrens Health Research Institute | Roberts S.,Alfred Hospital | Jones K.,Burnet Institute | And 18 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: HCV patients who fail conventional interferon-based therapy have limited treatment options. Dendritic cells are central to the priming and development of antigen-specific CD4+ and CD8+ T cell immunity, necessary to elicit effective viral clearance. The aim of the study was to investigate the safety and efficacy of vaccination with autologous dendritic cells loaded with HCV-specific cytotoxic T cell epitopes. Methods: We examined the potential of autologous monocyte-derived dendritic cells (MoDC), presenting HCV-specific HLA A2.1-restricted cytotoxic T cell epitopes, to influence the course of infection in six patients who failed conventional therapy. Dendritic cells were loaded and activated ex vivo with lipopeptides. In this phase 1 dose escalation study, all patients received a standard dose of cells by the intradermal route while sequential patients received an increased dose by the intravenous route. Results: No patient showed a severe adverse reaction although all experienced transient minor side effects. HCV-specific CD8+ T cell responses were enumerated in PBMC by ELIspot for interferon-γ. Patients generated de novo responses, not only to peptides presented by the cellular vaccine but also to additional viral epitopes not represented in the lipopeptides, suggestive of epitope spreading. Despite this, no increases in ALT levels were observed. However, the responses were not sustained and failed to influence the viral load, the anti-HCV core antibody response and the level of circulating cytokines. Conclusions: Immunotherapy using autologous MoDC pulsed with lipopeptides was safe, but was unable to generate sustained responses or alter the outcome of the infection. Alternative dosing regimens or vaccination routes may need to be considered to achieve therapeutic benefit. © 2010 European Association for the Study of the Liver.


Trickett A.E.,University of New South Wales | Wallz D.M.,Center for Blood Cell Therapies | Wallz D.M.,University of Melbourne
Pathology | Year: 2011

Use of cellular products for therapeutic purposes has predominantly been unregulated inAustralia until recently.Transplant of haemopoietic progenitor cells (HPC) for bonemarrowregeneration is now a routine treatment for many disorders with an establishedmechanismof facility accreditation.However, other cellular therapies do not have any formof accreditation, are not well evaluated and may be associated with significant risks. On 31 May 2011 the Therapeutic Goods Administration (TGA) implemented a long heralded regulatory biologicals framework for cell and tissue based therapies. The framework currently excludes human HPC, organs for direct transplantation and reproductive materials which are already covered by various forms of existing peer review and accreditation. This new framework is a practical approach for applying regulation based on the risk of the product to the recipient with four classes of product. Class 1 is reserved for the least regulated products and currently does not contain any proposed products. Class 2 will be for minimally manipulated products which will only require manufacturing compliance and evaluation against product and other mandatory standards before entry onto the Australian Register of Therapeutic Goods (ARTG). Class 3 and 4 products will bemore than minimallymanipulated and these cells and tissues may be used in a non-homologous manner. Class 3 and 4 products will represent a spectrum of risk where Class 4 therapies will represent the highest potential risk to the recipient, with the same requirements for Class 2 approvals but with additional requirements for comprehensive evaluation of a dossier for quality, safety and efficacy of the product. The extent of this quality, safety and efficacy data will depend upon the nature of the product and its associated risks, but will bemore comprehensive for Class 4 asopposedto Class 3 products. The only truly contentious feature of this framework is the extremely high cost for dossier evaluation and the puzzling absence of an orphan drug scheme for biologicals. © 2011 Royal College of Pathologists of Australasia.

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