This project will develop and test a new cell-based anticancer vaccine for patients with Prostate cancer. The collaboration will involve French, Italian, Austrian and German researchers. Blood will be taken from patients in the clinical trial, the patient's cells will be converted into a cell vaccine, and these cells will be labelled with a radioactive tracer and re-injected into the host. Australian researchers at the Centre for Blood Cell Therapies at the Peter MacCallum Cancer Centre will the ....This project will develop and test a new cell-based anticancer vaccine for patients with Prostate cancer. The collaboration will involve French, Italian, Austrian and German researchers. Blood will be taken from patients in the clinical trial, the patient's cells will be converted into a cell vaccine, and these cells will be labelled with a radioactive tracer and re-injected into the host. Australian researchers at the Centre for Blood Cell Therapies at the Peter MacCallum Cancer Centre will then track the performance of the vaccine using advanced diagnostic imaging to determine how effective the vaccine is in stimulating the body's own defence mechanisms to fight the cancer. Multiple versions of the treatment are being developed by the international collaboration and the Institute will help determine which approach is most effective in combating cancer. The Peter MacCallum Cancer Centre is the foremost centre worldwide for this type of cell tracking study.Read moreRead less
A Self-assembling And Self-adjuvanting Nanoparticular Therapeutic Vaccine Against Cervical Cancer
Funder
National Health and Medical Research Council
Funding Amount
$387,858.00
Summary
One in every three Australians will be diagnosed with cancer in their lifetime according to the Australia Cancer Foundation. The proposed project aims to develop pathogen-like bullets based on self-organized nanoparticles which would become a strong weapon against cervical cancer.
Optimising Immunity Towards Cancers By Vaccination.
Funder
National Health and Medical Research Council
Funding Amount
$211,320.00
Summary
In this project we will be studying the mechanisms of how an efficient anti cancer vaccine could be generated. We will be using cervical cancer associated human papillomavirus type 16 E7 protein as the model protein in an experimental vaccine model in mice. The results obtained from this project not only able us to design better vaccines against cervical cancers in women but against many other cancers and viruses.
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
Discovery Of Long CD8+ T Cell Epitopes Uncovers A Hidden Reservoir Of Immunodominant, Anti-tumour Responses
Funder
National Health and Medical Research Council
Funding Amount
$480,127.00
Summary
Stimulating killer T cells to eliminate tumours has been one of the ultimate yet elusive goals of cancer vaccine development. Vaccines aimed at stimulating killer T cells are similar to those generated under natural conditions. However, special strategies are needed to vaccinate beneficial killer T cells that are not normally part of the natural immunity. In this project, we will explore such a scenario and dissect the related mechanisms contributing to such differential immune outcomes.
A NOVEL APPROACH FOR TARGETING DNA TO DENDRITIC CELLS IN VIVO FOR VACCINE DEVELOPMENT AND CANCER IMMUNOTHERAPY
Funder
National Health and Medical Research Council
Funding Amount
$430,250.00
Summary
The use of genetic material, known as DNA, as a vaccine, has been a relatively new advance in vaccination technology with potential for combating many infectious diseases and cancers. The use of DNA has the advantage that it can be easily manipulated to develop new vaccines that have the desired preventative and-or immunotherapeutic effect. For optimal effect, however, the DNA to be used as a vaccine needs to be targeted to specific cell types in the body. Evidence suggests that a minor populati ....The use of genetic material, known as DNA, as a vaccine, has been a relatively new advance in vaccination technology with potential for combating many infectious diseases and cancers. The use of DNA has the advantage that it can be easily manipulated to develop new vaccines that have the desired preventative and-or immunotherapeutic effect. For optimal effect, however, the DNA to be used as a vaccine needs to be targeted to specific cell types in the body. Evidence suggests that a minor population of cells known as dendritic cells, which are present in blood and other tissues, play an important role in eliciting the effects of DNA vaccines. However, current methods for delivering DNA to these cells often lack selectivity in delivery, and-or use viruses to deliver the DNA. This can pose the risk of allergic type reactions and-or possibly cause tumours. The use of small membranous vesicles known as liposomes, made of phospholipids, has recently attracted considerable interest as DNA delivery vehicles, since these are considered safe, and have the potential to deliver large quantities of DNA. Although DNA can easily be packaged inside liposomes, it is has not been easy to target the liposomes and their contents (eg. encapsulated DNA) to specific cells (such as dendritic cells) within the body. We have recently produced a novel chelator lipid molecule which can be used to conveniently attach onto the liposome surface specific targeting molecules, such as engineered forms of antibody fragments, that can target or steer the liposomes together with their payload (eg. the DNA), directly to dendritic cells. This project will test the potential for using such targeted liposomes as DNA vaccines by examining whether liposomes containing DNA for a model antigen can be used in vaccinations to inhibit the growth and metastasis of a highly metastatic tumour (melanoma) in mice.Read moreRead less
Immunological Mechanisms Of Clinical Responsiveness To Immunotherapy For Metastatic Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
There have been no major improvements in the treatment of most metastasizing, solid tumours in the last several decades. One avenue that has received much attention is boosting a cancer patient's immune system with an anti-cancer vaccine, so that it destroys just the cancerous cells. This has proved an elusive goal, and no treatment has ever been shown to be of repeated worth, in the complete resolution of multiple sites of metastatic disease, until now. Two consecutive trials of our dendritic c ....There have been no major improvements in the treatment of most metastasizing, solid tumours in the last several decades. One avenue that has received much attention is boosting a cancer patient's immune system with an anti-cancer vaccine, so that it destroys just the cancerous cells. This has proved an elusive goal, and no treatment has ever been shown to be of repeated worth, in the complete resolution of multiple sites of metastatic disease, until now. Two consecutive trials of our dendritic cell based vaccine, which uses only cells from the patient to be treated, have each shown a 15% complete, durable, response rate. The remissions have now lasted longer than 3 years in patients otherwise expected to survive less than 1 year, with no serious side effects observed in any of the patients treated. It is likely that part of the success of this treatment is that it targets unique mutations in the patient's own cancer cells, in combination with a powerful immune stimulation from the dendritic cells. In contrast, most carefully run trials, now and in the recent past, have attempted to use more generic targets, common to many patients' cancers. The problem with this approach is likely to be that the patient is tolerant to these, since the targets are common, self proteins. At variance with all previous trials, we found an exact correlation between durable clinical responses and the degree of anti-tumour immunity displayed by the patients T cells. This grant proposal is based on the reasoning that, by studying in depth the characteristics of this successful immune response, in patients with complete, durable, clinical responses, we will be able to make major improvements in the formulation of the therapy.Read moreRead less
Targeting Human Dendritic Cells In A Multiple Myeloma Humanized NOD/SCID Model
Funder
National Health and Medical Research Council
Funding Amount
$425,696.00
Summary
Adoptively transferred dendritic cells (DC) loaded with tumor associated antigen (TAA) have been shown to induce anti-tumor immunity in animal models; however, their therapeutic efficacy in cancer patients has not been established. Protective immunity has failed in the tumor-bearing host and the ability of human DC to induce anti-tumor responses in the abnormal environment of the cancer patient requires further investigation. Due to the limited capacity to investigate the DC-tumor interaction in ....Adoptively transferred dendritic cells (DC) loaded with tumor associated antigen (TAA) have been shown to induce anti-tumor immunity in animal models; however, their therapeutic efficacy in cancer patients has not been established. Protective immunity has failed in the tumor-bearing host and the ability of human DC to induce anti-tumor responses in the abnormal environment of the cancer patient requires further investigation. Due to the limited capacity to investigate the DC-tumor interaction in patients, humanized animal models containing human DC and tumor provide an opportunity to obtain important new information. We propose to develop multiple myeloma (MM) as a human tumor in our humanized (hu)NOD-SCID model containing human DC, and to use this in vivo MM-huNOD-SCID model to restore immunity by correcting the human DC-tumor interaction.This knowledge will act as a fast track to select and design a new (simplified) DC-based immunotherapy to treat cancer patients and will be translated directly into our MM clinical trials program, potentially by targeting human DC based on CD205 recognition.Read moreRead less
Strategies To Enhance CD4 T Cell-mediated Anti-tumour Immunity
Funder
National Health and Medical Research Council
Funding Amount
$529,577.00
Summary
The immune system is capable of controlling cancer, but frequently does not do so. In this project we will study two factors that compromise anti-cancer immune responses: regulatory T cells, which suppress immune responses, and tolerogenic dendritic cells, which subvert potentially beneficial responses to tumours. By manipulating these factors, we hope to enhance the effectiveness of the immune response against cancer.