Cancer Immunotherapy Group Current Research

Project One: Regulation of the Immune Response by Perforin

One of the major obstacles to cancer immunotherapy is overcoming the mechanisms that limit current anti-tumour immune responses. We have observed that elimination of dendritic cells by perforin, a protein produced and released by cytotoxic T lymphocytes (CTLs), prevents them from restimulating anti-tumour immune responses.

Early results indicate that while normal CTLs expand little after dendritic cell immunisation, do not increase their ability to secrete cytokines and inhibit the proliferation of other naïve CD4+ and CD8+ T cells, the opposite is true for CTLs that cannot make perforin. This suggests that perforin plays an important role in regulating the outcome of immune responses.

Recently we have shown that the sensitivity of dendritic cells to killing is dependent on how they are loaded with antigen. We are now looking to see if we can take advantage of this information to improve current dendritic cell vaccine design.

We have also launched a new project to investigate how activated CD8+ T cells can inhibit allergic airway inflammation and the role perforin-dependent killing may play in this pathway(s).

Project Two: Intratumoural Antigen Presenting Cells

We are characterising the phenotype and function of immune cells present within unmanipulated tumours. Interestingly, although dendritic cells isolated from tumours were shown to be functional in antigen uptake, they did not activate tumour-specific CD4+ and CD8+ T cells in vitro.

We have now extended this study by demonstrating that the inability of the tumour-infiltrating dendritic cells to activate T cells does not appear to be due to the presence of high numbers of suppressive T regulatory cells in the tumours, because depletion of the T regulatory cells did not reverse this effect.

Project Three: Chronic Lymphocytic Leukaemia (CLL) Clinical Study

In December 2007 Haematologist Dr Robert Weinkove launched the Malaghan Institute's first clinical study into CLL, the most common blood cancer in New Zealand. Working in conjunction with the Wellington Blood and Cancer Centre, and Dr Ian Hermans, Dr Weinkove will compare the immune systems of patients with CLL with those of healthy volunteers. The focus of this study is a rare type of blood cell called the natural killer T (NKT) cell, which Dr Weinkove believes could be used to improve responses to cancer vaccination.

Project Four: Survival of Dendritic Cell Subpopulations after alpha-GalCer Administration

Presentation of alpha-GalCer, which is used in dendritic cell vaccines to enhance the anti-tumour immune response, leads to the activation of natural killer T (NKT) cells. We wished to determine whether NKT cells can kill dendritic cells after vaccination and found that alpha-GalCer administration stimulates the disappearance of a subpopulation of spleen dendritic cells. The mechanism of dendritic cell disappearance did not involve perforin but instead appears to be partly mediated by the cytokine TNF-alpha. The significance of this discovery with respect to vaccine design is currently being investigated.

Project Five: Memory T cells in Cancer Immunotherapy

We have characterised populations of tumour-specific T cells that are long-lived yet still effective at fighting tumours. We are currently attempting to define the conditions required to generate these cells in culture. We are also collaborating with proteomic specialists from Victoria University's Centre for Biodiscovery to examine the proteins expressed by these cells. It is anticipated that this information will be highly beneficial for the generation of more effective tumour specific T cells and vaccines.

 

Collaborators

Dr Gib Bogle, A/Prof Rod Dunbar, Maurice Wilkins Centre, Auckland, New Zealand 

Prof Bill Denny, Auckland Cancer Society Research Centre, The University of Auckland, New Zealand

Dr Bill Jordan, Dr Pisana Rawson, Dr Lifeng Peng, Centre for Biodiscovery, Victoria University of Wellington, New Zealand

Dr Bronwyn Kivell, Victoria University of Wellington, New Zealand

A/Prof Christiane Ruedl, Nanyang Technological University, Singapore

Prof Joe Trapani, Peter MacCallum Institute, Melbourne, Australia

A/Prof John Carter, Wellington Cancer Centre

 

Funding Sources

Cancer Society of New Zealand

Genesis Oncology Trust

Haematology Society of Australia and New Zealand

Health Research Council of New Zealand

Infinity Foundation Ltd

Leukaemia and Blood Foundation

New Zealand Lottery Health Research

The Royal Society of New Zealand Marsden Fund

University of Otago

Victoria University of Wellington

Wellington Division of the Cancer Society

Wellington Medical Research Foundation