Searching for key immune markers
Our researchers are focussed on discovering key immune markers and biological processes which will provide new diagnostic and therapeutic products for improving patient care.
Investigating the Function of the C-Type Lectin Receptor CD302 in Dendritic Cells
Primary Supervisor: Dr Pablo Silveira Auxiliary Supervisor: A/Prof Georgina Clark
Dendritic cells (DC) serve critical roles in detecting pathogens and initiating relevant adaptive immune responses. Their ability to traffic from tissues into lymphoid organs are central to this function. We identified the novel C-type lectin receptor CD302, generating the first knockout (KO) mouse to reveal a role in DC migration.
The project aims include contributing to production of a monoclonal antibody to mouse CD302 and using it to examine DC expression and alteration. Animal work, tissue culture, flow cytometry and microscopy will be used to study DC function in CD302KO mice and characterise its newly identified ligands. The project will provide valuable knowledge into CD302 and assess its potential as a therapeutic target on DC for preventing inflammatory diseases.
CD300e and CD300f as Novel Immune Regulatory Molecules to Control Tumour Growth
Primary Supervisor: A/Prof Georgina Clark Auxiliary Supervisor: Dr Pablo Silveira
CD300e is a sphingolipid binding and CD300f is a ceramide binding immunoregulatory molecule. Expression of each is restricted to myeloid cells. Their restricted expression, and ability to regulate inflammatory micro-environments, makes them attractive therapeutic targets for manipulation of myeloid responses, including tumour suppressor myeloid cells. The aims of this project are to compare 1). the phenotype of our CD300e-deficient or CD300f-deficient mice and wildtype mice and 2). their ability to regulate anti-tumour responses.
The student will learn broad laboratory skills including flow cytometry, real-time PCR, cell culture, isolation of leucocyte populations through magnetic- and fluorescence-activated cell sorting and optimisation of mouse tumour models. The studies will contribute to our understanding of the mechanisms by which CD300e and CD300f modulate tumour microenvironments.
THE DENDRITIC CELL SURFACE
We seek to understand the cell surface phenotype of the human blood dendritic cell (BDC) populations. There is still a paucity of mAbs to dendritic cell molecules that can be used to positively select the cells. A select few mAbs bind molecules that, in many cases, have unknown identity and function however they are useful in discriminating different BDC populations. The function of the molecules identified with DC specific mAbs remains unknown in many cases. Our pathway to understanding the BDC surface and the molecular landscape is to combine studies using human cells in vitro models or xenogeneic in vivo models with specific mouse models. We focus on molecules that we were the first to identify and target a number of key molecules and antibodies that we are investigating in depth.
- CD300 family of immune regulatory molecules
- CD302 ; the simplest C-type lectin
- The CMRF-44 antigen
- The CMRF-56 antigen
TARGETING NOVEL MOLECULES WITH NOVEL MONOCLONAL ANTIBODIES
Therapeutic mAbs are the fastest growing biological class. We are using our portfolio of novel mAbs to understand how each can be used as a therapeutic in the treatment of haematological cancers. Our mouse mAbs are being engineered into human chimeric mAbs, humanised or new mAbs selected from human phage libraries. We are focusing on two areas in particular.
- We are investigating ways of treating acute myeloid leukemia with myeloid specific mAbs using antibody drug conjugates and other antibody derivatives. We have three molecules we are targeting to treat AML.
- Checkpoint inhibitors have been used with great success in oncology. However their success has been limited to a limited number of cancer types and a limited group of patients. Antibodies targeting other checkpoint inhibitors are also likely to be successful. We are pursuing the use of mAbs to inhibitory molecules as novel checkpoint inhibitors.
DC VACCINATION FOR CANCER IMMUNOTHERAPY
Using DC to re-educate the immune response to cancer has long been a holy grail Many clinical trials have been completed which whilst demonstrating safety have been disappointing in their efficacy. Most DC trials have used the monocyte derived DC (MoDC). One of the most successful trials used a DC preparation derived from blood cells. We have long argued that MoDC do not represent the gold standard DC and that a preparation of BDC will provide an enhanced DC vaccine.
- We are have developed a BDC purification platform using one of our novel mAbs, CMRF-56, that results in an effective DC preparation for DC vaccination. We are optimising these cells for vaccines to treat castrate resistant prostate cancer, glioblastoma multiforme, colorectal cancer and acute myeloid leukemia.
- In vivo targeting of antigen to DC will be a cost efficient therapy. Our novel DC mA target internalised molecules. We are using them to deliver antigen to DC in induce anti-tumour responses.