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.
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.
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
Towards Effective Immunotherapy Of Cancer Using Genetically Enhanced Lymphocytes
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Immunotherapy is a potentially powerful and specific form of cancer therapy that may be more effective and have fewer side effects than current forms of therapy including chemotherapy and radiotherapy. Already dramatic responses have been observed in a proportion of patients receiving immunotherapy for some malignancies but these responses are all too infrequent. T cells constitute an important part of the immune system but they often fail to recognize cancer and do not respond strongly enough a ....Immunotherapy is a potentially powerful and specific form of cancer therapy that may be more effective and have fewer side effects than current forms of therapy including chemotherapy and radiotherapy. Already dramatic responses have been observed in a proportion of patients receiving immunotherapy for some malignancies but these responses are all too infrequent. T cells constitute an important part of the immune system but they often fail to recognize cancer and do not respond strongly enough against tumours. This project investigates the feasibility of endowing patients' T cells with the abilities to recognize cancer and respond vigorously against it by genetically modifying the T cells. In this study, T cells are removed from mice that have cancer and a gene encoding an anti-cancer molecule inserted into the T cells. The T cells are activated, grown to large numbers and given back to tumour-bearing mice followed by booster vaccinations. The strategy used is novel and the proposed studies, together with preliminary data, represent the first investigations of their type in the world. Information derived from these studies will extend our understanding of tumour immunology and provide an appreciation of the importance of various parameters in achieving anti-tumour responses. Improved anti-tumour responses achieved through investigations in these proof-of-principle pre-clinical models could lead to more effective immunotherapeutic regimens in patients.Read moreRead less
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
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