A Tumor Specific Variant Of The EGFR: Characterization And Target For Immunotherapy.
Funder
National Health and Medical Research Council
Funding Amount
$85,570.00
Summary
Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. This therapeutic approach requires an antibody that specifically binds to cancer cells ....Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. This therapeutic approach requires an antibody that specifically binds to cancer cells but not normal cells. In this proposal, we wish to test a novel antibody that binds to a protein on the cell surface called the EGF receptor. While the EGF receptor is found on the surface on many cells, our antibody recognizes a modified version of the EGF receptor that is found exclusively on cancer cells. Previous EGF receptor antibodies tested in the clinic all recognized the normal EGF receptor and thus proved unsuitable as they bound to cells in the liver causing significant side effects. It is anticipated that the specificity of our novel antibodies will overcome this problem. Eventually this antibody could be used to treat patients with brain, breast, prostate and lung cancer. We will also conduct a number of studies to determine the function of this modified receptor. This work will improve our understanding of those events associated with development of tumors.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.
Using Genetically Manipulated Mice To Study The Pathophysiologic Consequences Of Castration-induced Prostatic Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
Prostate cancer is the second leading cause of cancer death among Australian men. The disease is incurable once it spreads beyond the confines of the prostate gland. Hormonal treatments can keep the cancer at bay for a number of years until they are no longer effective. Hormonal treatments cause shrinkage of prostate cancer because they interfere the function of the male hormone, testosterone, which encourages growth of prostate cancer. Hence, there is a need for other treatments that may improv ....Prostate cancer is the second leading cause of cancer death among Australian men. The disease is incurable once it spreads beyond the confines of the prostate gland. Hormonal treatments can keep the cancer at bay for a number of years until they are no longer effective. Hormonal treatments cause shrinkage of prostate cancer because they interfere the function of the male hormone, testosterone, which encourages growth of prostate cancer. Hence, there is a need for other treatments that may improve the quality of life and survival of prostate cancer patients. It appears that a cancer patient can make immune cells known as T cells, which can recognise his own tumour but which are prevented from destroying the tumour. Using a mouse model of prostate cancer, we wish to understand how prostate tumours act to prevent immune destruction in circumstances that are common to the treatment of human prostate cancer. For example, hormonal treatments produce dead prostate cancer cells that will be cleared by the body's professional scavenger cells in a way that suppresses an active immune response against the tumour. To learn how the removal of dead cells suppresses the immune response, we propose to perturb the normal clearance of dead prostate cells by at least two means. First, we will study mice that have an inherited deficiency in the removal of dead cells. Second, these mice will be given a growth factor to produce an excess of immune stimulating cells known as dendritic cells in the prostate gland. The dendritic cell is the main type of cell that initiates immune responses. We will investigate whether the greater number of dendritic cells, which were put into the prostate gland by the growth factor, can remove the dead prostate cells in a way that excites rather than suppresses the anti-tumour immune response. Positive results obtained from these studies may lead to the design of new treatments for advanced prostate cancer.Read moreRead less
Mechanisms Of T Cell Migration And Interactions In Tumours
Funder
National Health and Medical Research Council
Funding Amount
$609,385.00
Summary
Cancer is still a leading cause of death. Thus, there is great need to develop improved anti-cancer therapies, which could be achieved by boosting the body's own resources, i.e. the immune system. Using a functional imaging approach, i.e. two-photon microscopy, we will directly visualise how tumour cells are attacked by the immune system. Mechanistic insight into this process will serve as a basis for the development of improved immuno-therapeutic strategies that aim to target cancer cells.
Novel Approaches For Activation And Expansion Of Genetically Modified T Cells In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$115,660.00
Summary
Killer T lymphocytes can penetrate tumors and their propagation and transfer into cancer patients has demonstrated some encouraging results, but this form of adoptive immunotherapy remains 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. Our previous work has indicated that killer T lymphocytes can be genetically engi ....Killer T lymphocytes can penetrate tumors and their propagation and transfer into cancer patients has demonstrated some encouraging results, but this form of adoptive immunotherapy remains 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. Our previous work has indicated that killer T lymphocytes can be genetically engineered in culture with tumor recognition receptors. When transferred into mice, these genetically engineered cells can release toxic and inflammatory proteins that cause tumor destruction. In this proposal we wish to further test this approach in mice by enginneering the mouse killer T cells with (i) receptors that provide stronger signals for killing and proliferation; and (ii) with receptors targeting other structures on tumor cells including the tumor vasculature as a means to overcome tumor escape. In addition, we wish to test a novel approach of combining both genetic engineering and vaccination strategies for expanding gene-modified cells after adoptive transfer. These studies will allow the best receptor genes to be transferred to human white blood cells and examined for anti-tumor effects in immune-deficient mice.Read moreRead less
Cancers have been found to contain 'stem cells' which are responsible for tumours growing and spreading throughout the body. Cancer therapies often target the cancer, but it is now clear the these treatments will only be effective if they can eradicate the malignant stem cells. This research investigates the best way of 'targeting' cancer stem cells in malignant melanoma as a means of developing more effective anti-cancer treatments.
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
Immunoregulatory Immune Responses To A Peripherally Presented Tumour Antigen
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
Tumours express proteins which the body can recognise as foreign. However, the recognition process often goes wrong, leaving the body's defences against infection unable to respond to the tumour. This lack of response may become permanent, and the tumour may then be protected by the immune system. We have a model system, based on cervical cancer, in which we can determine the reasons why tumour tolerance can occur, and explore ways of overcoming the tolerance
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