The Dendritic Cell Research group (DCR) is directed by Associate Professor Georgina Clark. They discover key immune markers and biological processes which will provide new diagnostic and therapeutic products for improving patient care.
The immune system controls and regulates our internal and external environmental reactions. It responds by up-regulating or activating cellular and soluble components to fight infection and cancer.
Dendritic cells (DC) are unique white blood cells that exist as different subsets throughout the body. They are responsible for initiating and directing immune responses.
As one of the pioneering groups in this field, the DCR is continuing to define human DC subsets and elaborate their function. The group studies DC surface molecules to determine how these molecules influence DC function and how antibodies targeting them might be used in clinical practice.
“If we understand how the dendritic cell starts or stops immune response, then we may be able to controls them for therapeutic purposes. We can increase their activity for vaccination and dampen their activity to allow tissue transplantation and control autoimmune disease” Professor Derek NJ Hart, early 1980s.
DCR was established at the ANZAC Research Institute, University of Sydney by Professor Derek Hart and Associate Professor Georgina Clark in 2010. They continued their research into the cell surface phenotype of human dendritic cells, developing monoclonal antibody (mAb) based therapeutics as immune therapies for the treatment of haematological malignancies and solid organ cancers. As a translational research laboratory, DCR hosts postdoctoral fellows, clinical and basic science PhD students and a strong administrative team. Their intellectual property is managed by DendroCyte BioTech Pty Ltd providing support through commercialisation. DCR works in close collaboration with haematologists and oncologists through Royal Prince Alfred, Concord Repatriation General Hospitals and Lifehouse.
In December 2017, unable to overcome cancer himself, the DCR sadly lost Professor Hart. DCR now continues their work to ensure his legacy will be DC based therapies to treat those with cancer.
A major part of our work is aimed at using the patient’s immune responses to treat haematological cancers. We are testing our findings in preclinical models of stem cell transplantation, leukaemia, multiple myeloma, prostate cancer and other malignancies.
The core of DCR is using monoclonal antibodies to novel molecules. DCR has played vital roles in the Human Leucocyte Differentiation Antigen Workshops providing leadership to the organisation that aims to provide a structure to ensure validation of monoclonal antibodies to leucocyte surface molecules.
We are striving to develop novel immunosuppressive strategies, including our previous anti-CD83 antibody as a novel therapeutic agent. We aim to use this antibody to improve transplant outcomes, whilst preserving the patient’s ability to fight infections and cancer. Negotiations to support a clinical trial of anti-CD83 in allogeneic haematopoietic stem cell transplantation are underway.
There are three broad research areas within the group.
1. 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
2. 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.
Acute graft versus host disease is a life threatening complication of haematopoietic cell transplantation. We have shown that targeting activated DC prior to transplant prevents aGVHD. We have developed a human anti-human mAb that can be used to deplete activated DC and we are continuing mechanistic studies to understand how this works. We are preparing to take the mAb to Phase I clinical trial to test its safety and efficacy. We are also considering ways to use this mAb as a therapeutic as an immune suppressive in solid organ transplantation and other haematological malignancies.
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.
3. 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.