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The Role Of CD4+ T Cells In The Tumour Killing By CD8+ Memory T Cells.
Funder
National Health and Medical Research Council
Funding Amount
$303,000.00
Summary
It has been observed that human cancers grow in spite of the presence of tumour antigen specific memory CD8+ tumour killer T cells in the body. These memory killer cells are unable to kill the cancer. Our research work in a mouse model indicates that the CD8+ T cells can be activated to kill cancers if cancer antigen specific CD4+ T helper cells are activated. The mechanism how this happens is not clear. The role of regulatory or suppressor CD4+ T cells are also not known. In this proposal we wi ....It has been observed that human cancers grow in spite of the presence of tumour antigen specific memory CD8+ tumour killer T cells in the body. These memory killer cells are unable to kill the cancer. Our research work in a mouse model indicates that the CD8+ T cells can be activated to kill cancers if cancer antigen specific CD4+ T helper cells are activated. The mechanism how this happens is not clear. The role of regulatory or suppressor CD4+ T cells are also not known. In this proposal we wish to study the mechanism of how CD8+ memory T cells get activated to cancer killer cells by the CD4+ T helper cells. This information will help us to design better immunotherapies for cancer patients.Read moreRead less
Mechanisms Of Action Of The Antigen Presenting Cells That Impair Lymphoma-specific Cytotoxic T Lymphocytes
Funder
National Health and Medical Research Council
Funding Amount
$295,983.00
Summary
Our immune systems are continually fighting cancer. However, the cancer cells occasionally acquire mutations that enable them to subvert the immune system. Usually they do this by hiding under the appearance of normal tissue, but sometimes they activate the very mechanisms that are in place to shut-down immune responses when these are no longer necessary. The goal of this proposal is to identify such mechanisms and find ways of bypassing them, thus restoring anti-tumour activity in patients.
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
IMMUNOTHERAPY OF MELANOMA WITH DENDRITIC CELL VACCINES
Funder
National Health and Medical Research Council
Funding Amount
$496,980.00
Summary
Melanoma is a skin cancer which continues to increase in incidence in Australia. It is a significant cause of morbidity and mortality because of its tendency to spread from skin to other body sites. It is largely resistant to chemotherapy. Immunological approaches to its treatment hold promise but there is a need to develop more effective vaccines to assist in treatment. Preliminary studies suggest that injection of dendritic cells primed with melanoma antigens induce strong immune responses and ....Melanoma is a skin cancer which continues to increase in incidence in Australia. It is a significant cause of morbidity and mortality because of its tendency to spread from skin to other body sites. It is largely resistant to chemotherapy. Immunological approaches to its treatment hold promise but there is a need to develop more effective vaccines to assist in treatment. Preliminary studies suggest that injection of dendritic cells primed with melanoma antigens induce strong immune responses and regression of melanoma. If this can be confirmed it will represent a significant advance in treatment of the disease. The studies in the proposal are to investigate whether a new form of treatment based on immunisation with dendritic cells sensitised with tumour antigens will prove to be more effective than existing treatments. Dendritic cells are responsible for stimulating immune responses and are grown from the patient's blood. They are then sensitised with tumour antigens and injected into the lymph nodes of the patient. The study will also measure immune responses during the immunisation procedure and assess whether these measures can predict clinical responses in the patient. If the study is successful in its objectives it will assist in development of more effective treatment of melanoma.Read moreRead less
A Vaccine To Break Tolerance To Cervical Carcinoma Oncoprotein
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Evidence that cervical cancer is caused by Human Papillomavirus is compelling. Once the virus enters the cells of the cervix, it produces a protein named E7 which functions to make the cells cancerous. Cervical cancer is the fifth commonest cause of death in women in Australia, and the major killer of women world-wide. The E7 protein is the ideal target for a vaccine since it occurs only in the tumour cells. Cervical tumour cells are killed by specialised immune system cells termed CTLs which re ....Evidence that cervical cancer is caused by Human Papillomavirus is compelling. Once the virus enters the cells of the cervix, it produces a protein named E7 which functions to make the cells cancerous. Cervical cancer is the fifth commonest cause of death in women in Australia, and the major killer of women world-wide. The E7 protein is the ideal target for a vaccine since it occurs only in the tumour cells. Cervical tumour cells are killed by specialised immune system cells termed CTLs which recognised fragments of the E7 molecule on their surface, bound to 'self' MHC molecules. Our laboratory has developed several mouse models of human cervical cancer, and has worked out which parts of the E7 protein are important in developing an appropriate immune response to control tumour growth. However a major finding is that the E7 molecules render the CTL cell population incapable of making an appropriate response to kill the tumour cells. We believe that this process, termed 'tolerance induction' can be overcome by using a novel approach as follows. Specialised antigen presenting cells , termed 'dendritic cells' (DCs) will be isolated and made to produce E7 protein by infecting them with a geneticlly modified virus (Adenovirus) which expresses E7 and specialised DC activators molecules, but is incapable of itself replicating. The dendritic cells will be re-introduced into the host as a vaccine, and will present the E7 to the immune system in such a way that tolerance will be broken. In other words the vaccine recipient will again be able to make a CTL immune response to the E7 protein in their tumours, and so be able to kill the tumour cells.Read moreRead less
NK Cells As The Missing Link Between Anti-cancer Chemotherapy And CD8 T Cell Responses
Funder
National Health and Medical Research Council
Funding Amount
$488,478.00
Summary
Cytotoxic chemotherapy is the standard of care for most tumors but it rarely cures. The immune system has the capacity to destroy malignant cells but tumors usually evade immune destruction. Combination of chemo- immunotherapy may change this. DNA damage in tumor cells, caused by chemotherapy, induces expression of a set of molecules that activate Natural Killer cells. These cells can then activate anti-tumor T cells. Therapies that enhance this pathway may induce sustained anti-tumor effects.
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.