Cancer Immunotherapy

Staff
Funding
Collaborators
Student Projects
Recent Publications
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Lab Head: Dr Chris Schmidt
Chris.Schmidt@qimr.edu.au

Our principal aims are to develop, optimise, and apply immunologically based therapies for solid cancers by linking applied clinical research with basic investigations into the nature of cancer and immunotherapies.

Dendritic cell based immunotherapy
Cancer is the second leading cause of deaths in the Western World. The general course of disease and treatment is dependent on the cancer: the organs involved, the potential for spread (metastasis), the time course of growth, and the susceptibility to surgery, chemotherapy, radiotherapy, or (for some haematological malignancies) cellular therapies. While the efficacy of most of these has reached a plateau, the application of cell-based immunotherapies to solid and haematological malignancies has been a major area of recent growth. In general, these therapies are typified by requiring manipulation in the laboratory of human cells (usually tumour cells or blood-derived cells from the patient) before re-injection. The product either acts directly upon tumours (“passive” immunotherapies) or stimulates the patient’s immune system to kill or suppress the tumour cells (“active” immunotherapies, similar in concept to the familiar vaccines). Dendritic cells (DCs) are the body ’s natural activator of immune responses: all successful vaccines work via resident DCs. In cancer patients, the DCs may be dysfunctional, or the tumour itself may prevent them from activating an appropriate response. Activating patient DCs outside of the body can overcome these defects.

Melanoma (skin cancer) has been a particular focus of tumour immunotherapy research, having a long history of response to treatments based on the "vaccine" approach. In conjunction with the Mater Adult Public Hospital (Dr. Michael O’Rourke), we trialled autologous DCs, cultured ex vivo with irradiated, autologous tumour cells, as a treatment for patients suffering advanced metastatic melanoma. In the initial trial, 17 patients commenced immunotherapy, 12 of which received all six ‘priming’ vaccinations. Of these 12 patients, three have durable complete responses (CR), 3 had partial responses (PR), and the remaining 6 had progressive disease (PD; WHO criteria) (see figure for example of regressing tumours in CRs after DC immunotherapy). These results far exceed in number those reported for other active immunotherapy trials, and in tolerability and durability those reported for biochemotherapies. Importantly, the clinical results from this trial, and the lack of morbidity associated with treatment, have now been replicated in a follow-up study. This has encouraged us to embark upon a randomised, double blinded clinical trial using the same treatment for patients with earlier stage metastatic melanoma. The centres for this trial are the Mater Adult Public, Princess Alexandra, and Royal Brisbane Hospitals, and the Malaghan Institute in Wellington, New Zealand. This trial will allow us to further examine our original observations that effective clinical responses are accompanied by strong systemic anti-tumour immunity, which is maintained while the course of treatment continues.

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Encouraged by the promising results of autologous DC-based immunotherapy for melanoma, we have also initiated immunotherapy trials for other solid malignancies including:
• Prostate cancer (trial I) – conducted in collaboration with the Royal Brisbane Hospital (Dr Frank Gardiner), the University of Queensland, the Northern section of the Urological Society of Australia, and the Mater Medical Research Institute,
• Prostate cancer (trial II) – conducted in collaboration with the Royal Brisbane (Dr Frank Gardiner, Dr J. Yaxley) and Princess Alexandra (Dr D. Nicol) Hospitals.
• Glioblastoma – conducted in collaboration with the Royal Brisbane (Drs D.G. Walker and F. H. Tomlinson), Mater Adult Public (Dr. Michael O’Rourke), and Mater Children’s (Dr R. Campbell and Dr L. Atkinson) Hospitals.
These trials examine the safety, the effect on immune parameters, and clinical efficacy of immunotherapy for each of the diseases. As with the melanoma trial, each immunotherapy consists of cultured autologous DCs presenting tumour cell antigen. Both prostate cancer trial II and the glioblastoma trial use irradiated, autologous tumour cells as the source of antigen. Alternatively, prostate cancer trial I uses a synthetic source of antigen and in addition aims to determine the optimal route for DC delivery.

Cytokine based (locally delivered) immunotherapy
An alternative to the use of ex-vivo cultured dendritic cells is to alter the tumour environment in situ, to enhance immune responses. Professor Kay Ellem in our group heads a team looking at this as an alternative strategy. His group is currently investigating the use of immortalized, non-cancerous cells which have been engineered to produce large amounts of biologically active molecules (cytokines). These cytokines can be involved in the development of systemic anti-tumour immune responses and anti-angiogenesis (antagonism to the growth of newly-formed tumour blood vessels). These cytokine-producing cells can be encapsulated in a biologically-inert naturally occurring polymer, forming microcapsules which can then be injected into actively growing tumour deposits. These microcapsules have the potential to de-bulk large tumour deposits, while enhancing anti-tumour immunity, leading possibly to the cure of pre-existing tumours and the long-term prevention of recurrence. If successful, this will have been achieved without the quality of life-reducing effects associated with chemo and radiotherapy. It is envisaged that this therapy may prove useful for patients with late-stage cancer who have a very poor prognosis and for whom few therapeutic avenues currently exist.

Staff

Labheads:	Dr Chris Schmidt Emeritus Professor Kay AO Ellem	Chris.Schmidt@qimr.edu.au Kay.Ellem@qimr.edu.au
Research Officer:	Dr Nathan Martinez	Nathan.Martinez@qimr.edu.au
Research Assistants:	Cathy Lanagan Linda O’Connor	Cathy.Lanagan@qimr.edu.au Linda.OConnor@qimr.edu.au
PhD Scholars:	Dr Michael Hamilton Dr Quan Huang Michelle Neller Michael Lai	Michael.Hamilton@qimr.edu.au Quan.Huang@qimr.edu.au Michelle Neller@qimr.edu.au Michael.Lai@qimr.edu.au

Funding

We are grateful for the support from the following agencies:
• Queensland Cancer Fund http://www.qldcancer.com.au
• Urological Society http://www.urosoc.org.au
• Atlantic Philanthropies http://www.atlanticphilanthropies.org
• NHMRC http://www.health.gov.au/nhmrc

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Collaborators

Dr. Michael E.G. O’Rourke (Mater Adult Hospital)
Dr. Mark Smithers (Princess Alexandra Hospital)
Dr. Barry O'Loughlin (Royal Brisbane Hospital)
Dr. David Ritchie (Malaghan Institute, Wellington, New Zealand)
Prof. Frank Gardiner (Royal Brisbane Hospital)
Dr. Andrew Brooks (University of Melbourne)
Dr. Thomas Wölfel (University of Mainz, Mainz, Germany)
Dr. Richard Laherty (QIMR)
Drs D.G. Walker (Royal Brisbane Hospital)
F. H. Tomlinson (Royal Brisbane Hospital)

Student Projects

Research projects are available within the Cancer Immunotherapy Laboratory for BSc Honours, MMedSci and PhD students interested in working on the biology of cancer DC-immunotherapy.

Recent Publications

O'Rourke MGE, Johnson M, Davern D, See J, Yang J, Bell JR, Slater GJ, Kerr BM, Crowe B, Purdie DM, Elliott SL, Ellem KAO, Schmidt CW. Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine. Cancer Immunol. Immunother., 52: 387-395, 2003. [pubmed abstract]

Ladhams A, Schmidt C, Sing G, Butterworth L, Fielding G, Tesar P, Strong R, Leggett B, Powell L, Maddern G, Ellem K, and Cooksley G. Treatment of non-resectable hepatocellular carcinoma with autologous tumour-pulsed dendritic cells. J Gastroenterol Hepatol, 17:889-96, 2002.[pubmed abstract]

Metharom P, Ellem KA, Schmidt C, Wei MQ. Lentiviral vector-mediated tyrosinase-related protein 2 gene transfer to dendritic cells for the therapy of melanoma. Hum. Gene Ther., 12:2203-13, 2001. [pubmed abstract]

Kikuchi A, Nieda M, Schmidt C, Koezuka Y, Ishihara S, Ishikawa Y, Tadokoro K, Boyd A, Juji T, Nicol A. In vitro anti-tumour activity of b-galactosylceramide stimulated human invariant Va24+NKT cells against melanoma. Br. J. Cancer 85 :741-6, 2001. [pubmed abstract]

Sherritt MA, Gardner J, Elliott SL, Schmidt C, Purdie D, Deliyannis G, Heath WR, and Suhrbier A. Effect of pre-existing cytotoxic T lymphocytes on therapeutic vaccines. Eur. J. Immunol., 30, 671-677, 2000. [pubmed abstract]

Mateo L, Gardner J, Chen Q, Schmidt C, Down M, Elliott SL, Pye SJ, Firat H, Lemonnier FA, Cebon J and Suhrbier A. An HLA A2 Polyepitope Vaccine for Melanoma Immunotherapy. J. Immunol. 163, 4058-4063, 1999. [pubmed abstract]

Ellem K, Schmidt C, O’Rourke M. Issues posed by tumour heterogeneity in trials of immunotherapy for late stage cancer. Cancer Forum 23:101-4, 1999.

Misko IS, Cross SM, Khanna R, Elliott SL, Schmidt C, Pye SJ and Silins SL. Crossreactive recognition of viral, self, and bacterial peptide ligands by human class I-restricted cytotoxic T lymphocyte clonotypes: Implications for molecular mimicry in autoimmune disease. Proc. Natl Acad. Sci. U.S.A. 96, 2279-2284, 1999. [pubmed abstract]

Zehntner S, Townsend W, Parkes J, Schmidt C, Down M, Bell J, Mulligan R, O'Rourke M, Ellem K, Thomas R. Tumour metastasis biopsy as a surrogate marker of response to melanoma immunotherapy. Pathology 31, 116-22, 1999. [pubmed abstract]

Silins SL, Cross SM, Krauer KG, Moss DJ, Schmidt CW, and Misko IS. A functional link for T cell expansions in healthy adults : evidence that persistent Epstein Barr virus infection causes major TCR perturbations in the peripheral blood repertoire. J. Clin. Invest. 102, 1551-8, 1998. [pubmed abstract]

Ellem KAO, O'Rourke MGE, Johnson GR, Parry G, Misko IS, Schmidt CW, Parsons PG, Burrows SR, Cross S, Fell A, Li CL, Bell JR, Dubois PJ, Moss DJ, Good MF, Kelso A, Cohen LK, Dranoff G and Mulligan RC. A case report: immune responses and clinical course of the first human use of granulocyte/macrophage colony stimulating factor transduced autologous melanoma cells for immunotherapy. Cancer Immunol. Immunother. 44, 10 20, 1997. [pubmed abstract]

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