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
T Cell Trafficking And Effective Immunotherapy For Cancer
Funder
National Health and Medical Research Council
Funding Amount
$218,807.00
Summary
Cancer is the major cause of death in Australia in 2007. New forms of treatment are needed. The body’s defences against infection can be harnessed to fight some cancers. This project will examine how we can do this better using the signals that tell the body’s killer cells where to go and what to do when they get there.
I am an immunologist studying the interaction between cancer and the immune system. I am involved in the development and characterization of immunotherapies for cancer.
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
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
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
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
WHAT IS THE RELATIVE ROLE OF TNF-RELATED APOPTOSIS-INDUCING LIGAND (TRAIL) IN TUMOR IMMUNITY?
Funder
National Health and Medical Research Council
Funding Amount
$85,660.00
Summary
Programmed cell death is a physiological process integral to the development and functioning of the immune system. A better understanding of the cellular effector cells and molecules that mediate cell death will provide valuable insight into designing better immunotherapeutic treatments of cancer. Members of the tumor necrosis factor (TNF) family of hormones and receptors are critically involved in the process of cell death. Within this family, several members have been well characterised and th ....Programmed cell death is a physiological process integral to the development and functioning of the immune system. A better understanding of the cellular effector cells and molecules that mediate cell death will provide valuable insight into designing better immunotherapeutic treatments of cancer. Members of the tumor necrosis factor (TNF) family of hormones and receptors are critically involved in the process of cell death. Within this family, several members have been well characterised and their functions ascribed. Some play an important role in the maintenance of immune cells , others in the movement of immune cells and organisation of lymphoid tissues. This proposal seeks to define the function of the recently discovered TNF-related apoptosis-inducing ligand (TRAIL). TRAIL mediates cell death of cancerous cells in culture but does not kill most normal tissues. This specificity for diseased tissue makes TRAIL a very promising candidate as an anti-tumor therapeutic. Until recently, very little was known regarding the natural physiological role of TRAIL. We have recently described the expression of TRAIL on liver natural killer cells and the anti-tumor activity of TRAIL against primary tumors and metastases. Importantly, TRAIL function appears to be regulated by an inflammatory mediator called interferon. We now wish to explore the role of TRAIL in tumor immunotherapies and tumor surveillance that requires interferon.Read moreRead less