Translational Oncology Laboratory

Current Research Projects

Cancer Immunotherapy Group

Pre-clinical development of CAR-T cell and BiTE therapies

CAR-T cell and BiTE therapies are revolutionising the treatment of certain blood cancers, which has spurred intense interest in extending these successes to the treatment of solid tumours. We have a pre-clinical program to develop CAR-T cell and BiTE therapy for solid cancers, with a particular focus on aggressive brain cancers (glioblastoma and diffuse midline glioma). We use patient-derived tumour and blood cells, as well as advanced mouse models and a novel tumour organoid system, to develop, optimise and test CAR-T cells for their ability to control tumour growth. Research programs in this area focus on identifying novel target antigens; improving the homing of CAR-T cells to tumour tissues; testing combination therapies; and optimising CAR-T cell survival and function.

CAR-T cell clinical trials

Our clinical program manufactures CAR-T cells targeting the GD2 tumour antigen here in Adelaide, using a protocol optimised through our pre-clinical research program. The GD2 molecule is expressed by many solid tumour types but has limited expression on healthy cells and tissues, making it an excellent CAR-T cell target. We have completed recruitment to a 12-patient trial of GD2-specific CAR-T cell therapy for patients with GD2-positive malignancies including melanoma and sarcoma (www.anzctr.org.au: ACTRN12613000198729).

Now, we have two active phase 1 clinical trials testing these GD2-targeting CAR-T cells in cancer patients. In the KARPOS trial (ACTRN12622001514796) at the Royal Adelaide Hospital, GD2-CAR-T cells are administered to patients with glioblastoma whose tumour has recurred despite previous surgery, chemotherapy, and radiotherapy. In the LEVI’S CATCH trial (ACTRN12622000675729) these CAR-T cells are given to children with brain tumours through a collaboration with Prof David Ziegler at the Sydney Children’s Hospital and Children’s Cancer Institute.

Understanding and predicting patient responses to Immune Checkpoint Inhibitor (ICI) therapy

ICI therapy is a new therapeutic approach that is now approved in Australia for the treatment of several cancer types, including melanoma, lung, and kidney cancers. These medicines can re-activate dormant anti-tumour immune responses, leading to dramatic tumour shrinkage, and possibly cure, in a fraction of patients. However, many patients receive little to no benefit, yet are still exposed to the risk of severe side effects. Using blood and tumour samples from melanoma and lung cancer patients, we are investigating the immune responses that underpin successful clinical outcomes following ICI therapy. This research may identify novel strategies to improve response rates, and is being used to develop a simple blood test to help guide the optimal treatment for each patient.

Exploring the microenvironment of brain tumours
Solid tumours don’t just contain cancerous cells, but are also infiltrated with a complex network of immune cells, blood vessels and other cell types. We have a research program focussed on understanding these cellular ecosystems in brain tumour patients, using techniques including single cell RNA sequencing, spatial transcriptomics, and high-parameter flow cytometry. These insights will allow us to optimise our immunotherapies to function optimally within challenging tumour microenvironments.

Antibody Targeting Group

First-line therapy for lung cancer typically involves cytotoxic chemotherapy, which is DNA-damaging and causes cancer cell death. We have preclinical proof of concept for a novel method of detecting cancer cell death using the APOMAB® monoclonal antibody that is specific for the essential La ribonucleoprotein overexpressed in malignancy.

We are currently investigating the following applications of APOMAB®:

• Antibody-drug conjugates (ADC) for bystander treatment of solid cancers: We are investigating ADC versions of APOMAB based on the premise that APOMAB-ADC-bound dead tumour cells are processed by both viable tumour cells and supporting leucocytes to produce bystander killing.
• Preclinical and clinical development of an imaging agent for detection of cancer cell death:  We have adapted the APOMAB® monoclonal antibody for use in immuno-positron emission tomography (PET). Non-invasive methods for detecting cancer cell death can be useful for the early evaluation of therapeutic responses. In this respect, a 20-patient phase 1 proof-of-concept immunoPET/CT trial has recently been completed at RAH (ACTRN12620000622909). APOMAB was radiolabelled with the diagnostic isotope Zirconium-89 (⁸⁹Zr). We found that its tumour uptake was greatest after prior treatment using cytotoxic chemotherapy or radiotherapy had induced cancer cell death.
• Using ADCs to stimulate anti-tumour immune responses in models of cancer: We are using ADCs alone and in combination with immunotherapy agents to both directly kill tumour cells and to modulate the body’s immune system to target and eliminate any remaining resistant cancer cells more effectively.
• Preclinical and clinical development of an APOMAB-CAR-T cell therapy: We have commenced preliminary experiments investigating the notion that APOMAB binding to dead cancer cells after a first step of standard anti-cancer treatment can provide a way of activating T cells.