Although the immune system has the ability to reject tumours, this sometimes does not occur, leading to cancer. There are many different types of cells that make up the immune system, including some which respond very early, called natural killer (NK) and NKT cells. These cells are the first line of defence against some tumours, although we do not understand how they recognise and respond to tumour cells. The aim of this project is to investigate the functional importance of both NK and NKT cell ....Although the immune system has the ability to reject tumours, this sometimes does not occur, leading to cancer. There are many different types of cells that make up the immune system, including some which respond very early, called natural killer (NK) and NKT cells. These cells are the first line of defence against some tumours, although we do not understand how they recognise and respond to tumour cells. The aim of this project is to investigate the functional importance of both NK and NKT cells in response to a range of different tumour types, including melanoma (skin cancer), lung carcinoma, breast carcinoma and sarcoma (connective tissue tumour). We will test the importance of each of these subsets by injecting these tumours into mice that have specific deficiencies in NK and-or NKT cells. If the NK or NKT cells are important, the tumours should grow more effectively when these immune cells are absent. We will also be able to put NK and-or NKT cells back into the mice to show directly that they are responsible for tumour rejection. Using a modification of this cell transfer approach, we will be able to inhibit special molecules that are normally produced by these cells that help them interact with other cells, and also help them attack the tumour cells. Collectively, the approaches outlined in this application allow us to determine which types of cells are important in response to a broad range of different tumour types, and also should tell us how these cells are able to attack the tumours. This information will be invaluable for the development of new strategies to use the patients immune system to attack cancer (known as immuno-therapy).Read moreRead less
WHAT IS THE RELATIVE ROLE OF TNF-RELATED APOPTOSIS-INDUCING LIGAND (TRAIL) IN TUMOR IMMUNITY?
Funder
National Health and Medical Research Council
Funding Amount
$85,660.00
Summary
Programmed cell death is a physiological process integral to the development and functioning of the immune system. A better understanding of the cellular effector cells and molecules that mediate cell death will provide valuable insight into designing better immunotherapeutic treatments of cancer. Members of the tumor necrosis factor (TNF) family of hormones and receptors are critically involved in the process of cell death. Within this family, several members have been well characterised and th ....Programmed cell death is a physiological process integral to the development and functioning of the immune system. A better understanding of the cellular effector cells and molecules that mediate cell death will provide valuable insight into designing better immunotherapeutic treatments of cancer. Members of the tumor necrosis factor (TNF) family of hormones and receptors are critically involved in the process of cell death. Within this family, several members have been well characterised and their functions ascribed. Some play an important role in the maintenance of immune cells , others in the movement of immune cells and organisation of lymphoid tissues. This proposal seeks to define the function of the recently discovered TNF-related apoptosis-inducing ligand (TRAIL). TRAIL mediates cell death of cancerous cells in culture but does not kill most normal tissues. This specificity for diseased tissue makes TRAIL a very promising candidate as an anti-tumor therapeutic. Until recently, very little was known regarding the natural physiological role of TRAIL. We have recently described the expression of TRAIL on liver natural killer cells and the anti-tumor activity of TRAIL against primary tumors and metastases. Importantly, TRAIL function appears to be regulated by an inflammatory mediator called interferon. We now wish to explore the role of TRAIL in tumor immunotherapies and tumor surveillance that requires interferon.Read moreRead less
CSF-1 Regulation Of Macrophage Adhesion And Motility And Promotion Of Tumour Invasion And Metastasis
Funder
National Health and Medical Research Council
Funding Amount
$323,453.00
Summary
Macrophages, a type of white blood cell, infiltrate tumours and encourage tumour cells to metastasize. The mechanism involves secretion of a macrophage motility factor, CSF-1, by the tumour cells and secretion of a tumour cell motility factor by the macrophages to stimulate co-migration, invasion and metastasis. CSF-1 controls macrophage motility via the CSF-1 receptor. Dissection of receptor signalling pathways to macrophage motility will identify therapeutic targets to prevent tumour spread.
Investigating Immune Regulation In The Tumour Microenvironment
Funder
National Health and Medical Research Council
Funding Amount
$288,650.00
Summary
Suppressive factors made by cells of the immune system or cancers themselves and immune regulatory T cells inhibit an effective anti-tumour response. My project aims to investigate the mechanism by which these factors and cells mediate their suppressive function. Understanding these processes in the cancer environment will allow the design of more effective cancer therapies.
Development Of Cancer Immunotherapy Using Gene-engineered T Cells In A Self-antigen Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$428,602.00
Summary
Killer T lymphocytes can penetrate tumours and their transfer into cancer patients has demonstrated some encouraging results, but this form of therapy and other approaches including vaccination remain ineffective in most cancer patients. In this project, we propose to improve the tumour trafficking and anti-tumour activities of killer cells by genetically engineering them with proteins that will enable them to recognise and destroy cancer cells.
Evaluation Of Immune Responses To Multiple Tumour Antigens During Tumour Growth
Funder
National Health and Medical Research Council
Funding Amount
$451,980.00
Summary
It is becoming increasingly clear that cancerous tissues are not hidden from the body's immune system and yet, despite the generation of tumour-specific T cells and antibodies, the immune system does not often destroy solid tumour. Tumours express a large number of potential antigens (molecules in or on cancer cells that can be recognised by the immune system), but T cell responses to tumour antigens may be limited to only a few of these antigens (the dominating ones). These T cells could compet ....It is becoming increasingly clear that cancerous tissues are not hidden from the body's immune system and yet, despite the generation of tumour-specific T cells and antibodies, the immune system does not often destroy solid tumour. Tumours express a large number of potential antigens (molecules in or on cancer cells that can be recognised by the immune system), but T cell responses to tumour antigens may be limited to only a few of these antigens (the dominating ones). These T cells could compete with any other T cells that have been, or are being, generated, preventing their expansion and development into fully functional T cells. If this is true, then tumours will 'escape' immune mediated destruction, as a T cell response to only a few antigens is not likely to be enought to seriously perturb growing tumours. In this grant we will use a well established mouse model of cancer to evaluate immune responses to tumour antigens during tumour growth and try to understand why other potential antigens do not invoke a fully functional immune response. If we are successful, we will have made advances that could lead to new therapies for cancer.Read moreRead less
The Role Of CD4+ T-helper Cells In The Generation, Maintenance And Activation Of A Long Lasting Anti-tumour CTL Effect.
Funder
National Health and Medical Research Council
Funding Amount
$247,383.00
Summary
In this research project we will be studying the mechanisms how a long-lasting anti-cancer response could be achieved by vaccination. This information not only will help to design better vaccines against cancers, but also will help to design better vaccines against viral diseases.
T Cell Trafficking And Effective Immunotherapy For Cancer
Funder
National Health and Medical Research Council
Funding Amount
$218,807.00
Summary
Cancer is the major cause of death in Australia in 2007. New forms of treatment are needed. The body’s defences against infection can be harnessed to fight some cancers. This project will examine how we can do this better using the signals that tell the body’s killer cells where to go and what to do when they get there.
Immunological Mechanisms Of Clinical Responsiveness To Immunotherapy For Metastatic Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
There have been no major improvements in the treatment of most metastasizing, solid tumours in the last several decades. One avenue that has received much attention is boosting a cancer patient's immune system with an anti-cancer vaccine, so that it destroys just the cancerous cells. This has proved an elusive goal, and no treatment has ever been shown to be of repeated worth, in the complete resolution of multiple sites of metastatic disease, until now. Two consecutive trials of our dendritic c ....There have been no major improvements in the treatment of most metastasizing, solid tumours in the last several decades. One avenue that has received much attention is boosting a cancer patient's immune system with an anti-cancer vaccine, so that it destroys just the cancerous cells. This has proved an elusive goal, and no treatment has ever been shown to be of repeated worth, in the complete resolution of multiple sites of metastatic disease, until now. Two consecutive trials of our dendritic cell based vaccine, which uses only cells from the patient to be treated, have each shown a 15% complete, durable, response rate. The remissions have now lasted longer than 3 years in patients otherwise expected to survive less than 1 year, with no serious side effects observed in any of the patients treated. It is likely that part of the success of this treatment is that it targets unique mutations in the patient's own cancer cells, in combination with a powerful immune stimulation from the dendritic cells. In contrast, most carefully run trials, now and in the recent past, have attempted to use more generic targets, common to many patients' cancers. The problem with this approach is likely to be that the patient is tolerant to these, since the targets are common, self proteins. At variance with all previous trials, we found an exact correlation between durable clinical responses and the degree of anti-tumour immunity displayed by the patients T cells. This grant proposal is based on the reasoning that, by studying in depth the characteristics of this successful immune response, in patients with complete, durable, clinical responses, we will be able to make major improvements in the formulation of the therapy.Read moreRead less
An Integrated Approach For The Efffective Adoptive Immunotherapy Of Cancer
Funder
National Health and Medical Research Council
Funding Amount
$468,119.00
Summary
Killer T lymphocytes can penetrate tumors and their transfer into cancer patients has demonstrated some encouraging results, but this form of immunotherapy remain ineffective in most cancer patients. We propose to improve the tumor trafficking and anti-tumor activities of killer cells by genetically engineering them with proteins that will enable them to recognise and destroy cancer cells. The outcomes of this project will validate this novel approach for treatment of cancer patients.