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
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
A Polyepitope HPV16 E7 DNA Vaccine Restricted Through Multiple Class 1 Haplotypes Protects Against E7-expressing Tumour
Funder
National Health and Medical Research Council
Funding Amount
$218,244.00
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 5th commonest cause of death in women in Australia, and the major killer of women world-wide.The disease is particularly severe in those women whose immune systems are impaired, indicating immunological control of the cancerous cells . Current therapies including surgical 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 5th commonest cause of death in women in Australia, and the major killer of women world-wide.The disease is particularly severe in those women whose immune systems are impaired, indicating immunological control of the cancerous cells . Current therapies including surgical removal are frequently inadequate, and the r is no effective drug to combat the virus.These observations indicate that a vaccine is warranted, and that the E7 protein may be an ideal target for the vaccine. Cervical tumour cells are killed by specialised immune system cells named CTLs which recognise fragments of foreign antigen(E7) on their surface bound to selfMHC molecules. Our work has shown that multiple antigen fragments can be encoded and stitched together in a genetic vaccine which will stimulate CTLs to function in a number of 'self'molecule situations Our laboratory has developed several mouse models of human cervical cancer , and (along with others) has worked out which parts of the E7 protein are importatnt in developing an appropriate immune response to control tumour growth when given as a vaccine. One animal model consists of mice which are genetically engineered to produce several types of selfmolecules and also E7. Thes mice develop skin tumours as result of E7 expression. This system provides model of cervical epithelial tumours caused by E7 expression in women.Thus we can ask the questions o can we elicit CTL responses which function in the context of humanself ? o Will these CTL responses prevent the growth of E7-induced epithelial tumours? The OUTCOME of the project will be a vaccine which will prevent the establishment of cervical cancer which can progress directly into clinical trials in women bearing appropriate selfmolecules.Read moreRead less
Improving Immunotherapy By Vascular Targeting And Barrier Alteration
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Tumors grow in part because they escape destruction by the immune system. New blood vessels grow inside tumors by a process called angiogenesis, which then stops cancer-fighting cells in their tracks. We hypothesise that breaking down the blood-tumor barrier will open tumors for attack by the cancer-fighting immune system. This proposal continues our work on reversal of angiogenesis in the context of immunotherapy. We expect these findings to lead to highly effective anti-tumor therapies.