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
The Structural Basis Of T Cell Recognition In The Context Of Lipid Presentation And The CD1 Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
CD1 molecules are critical in our host-defence against microbial pathogens. They survey our body for microbial lipids and then present them to our immune system for surveillance by T cell receptors. We aim to understand how a T cell receptor interacts with a CD1-lipid molecule. This interaction is crucial to the activation of our immune response and hence the elimination of the microbe. Once understood, this interaction can potentially be modified and has immunotherapeutic potential.
Analysis Of The Molecular Functions Of Perforin: A Critical Role In Tumor Immunosurveillance
Funder
National Health and Medical Research Council
Funding Amount
$318,916.00
Summary
Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer ....Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer cell function in these models. But the role for perforin expressing killer cells in tumor surveillance against spontaneous tumorigenesis is still hotly debated. Our proposal to study tumor development in perforin-deficient p53-mutant tumor prone mice will enable us to answer this question. Furthermore, the molecular mechanisms by which perforin functions are poorly understood. We therefore also propose to complete a structure-function analysis of perforin using unique tools and information that our laboratory has at its disposal. The long-term goal will be to better understand the function of perforin at the molecular level such that the rationale design of therapeutic perforin inhibitors may become a reality for future regulation of killer cell effector functions in disease.Read moreRead less
Role Of CD4 T Cells And APCs In The Induction And Maintenance Of An Effective Antitumor Response
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Many cancers are still untreatable by conventional therapies (surgery, chemotherapy and radiation). This includes malignant mesothelioma, a cancer associated with previous exposure to asbestos. Exposure can occur up to 30 years before the onset of this disease. The average time of survival for patients, from the time of diagnosis, is about nine months and the incidence of this disease is increasing. Novel therapies are therefore required to help alleviate this disease and perhaps eradicate it. I ....Many cancers are still untreatable by conventional therapies (surgery, chemotherapy and radiation). This includes malignant mesothelioma, a cancer associated with previous exposure to asbestos. Exposure can occur up to 30 years before the onset of this disease. The average time of survival for patients, from the time of diagnosis, is about nine months and the incidence of this disease is increasing. Novel therapies are therefore required to help alleviate this disease and perhaps eradicate it. Immunotherapy - using the body's own defence system to help fight cancer- is one potential form of new treatment. However we need to understand how the immune system and cancer normally interact with one another if we are to make rational decisions about the design of immunotherapies. We have established a laboratory model which allows us to investigate this interaction. We will determine which components of the immune system are required to eradicate cancer and at which stages of cancer growth they are most important. By understanding these pieces of the puzzle we may be able to tweak the system more appropriately or design vaccines that will be effective in at risk populations.Read moreRead less
The Role Of TGF-beta Signaling In Suppression Of Stat3-mediated Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$667,000.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach mining cells. Our proposal combines the expertise of the two investigators in signal ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach mining cells. Our proposal combines the expertise of the two investigators in signal transduction and the making of genetically modified mouse models. These strategies will be employed to specifically address in the laboratory mouse the function of two specififc signaling cascades, called Stat3 and TGF-beta. The identification of detailed description by which these molecules causally relate to cancer formation will provide clear and specific molecular targets for future therapies to treat various cancers, including those of the stomach.Read moreRead less
Differential Cooperation Of MAPKs With TGF-beta Signaling In Epithelial-Mesenchymal Transition
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
Tumor metastasis - the spread of tumor cells from the original site of growth to other sites in the body, is the biggest threat to survival for patients with solid tumors. The most damage change during cancer progression is the switch from a locally growing tumor to a metastastic killer. For biologist studying cancer, a major challenge is to identify the molecular and cellular mechanisms underlying the switch of non-invasive tumor to an invasive, metastatic state. This application aims to identi ....Tumor metastasis - the spread of tumor cells from the original site of growth to other sites in the body, is the biggest threat to survival for patients with solid tumors. The most damage change during cancer progression is the switch from a locally growing tumor to a metastastic killer. For biologist studying cancer, a major challenge is to identify the molecular and cellular mechanisms underlying the switch of non-invasive tumor to an invasive, metastatic state. This application aims to identify key molecular and cellular mechanism controlling this switch, with the ultimate aim being to devise treatments that inhibit tumor metastasis. The results from this work will provide clear and specific targets to prevent and to treat tumor metastasis. More importantly, the success of strategies used in this work can potentially be used clinically for tumor treatment.Read moreRead less
Novel Tools For The Imaging Of Tumor Hypoxia Using PET
Funder
National Health and Medical Research Council
Funding Amount
$727,856.00
Summary
Fast growing tumors often outgrow the ability of blood vessels to properly supply them with nutrients and oxygen. This creates tissue areas within the tumor that are lacking oxygen and are highly resistant to radiotherapy and chemotherapy. Imaging these areas using nuclear medicine techniques has now become important for therapy planning of cancer sufferers. This project aims to improve the properties of the existing agents in order to better select patients for a particular type of treatment.
Breast cancer is a common disease that is generally incurable if detected after it has spread to other organs. There is a lack of understanding of molecular events that drive the process. Cancers contain several types of host cells that contribute to the growth of the tumour, which can be regarded as wounds that never heal. Host cells are co-opted to promote continued growth of the cancer cells. It is the aim of this project to understand how these host cells promote the spread of breast cancer