Tougher Tests for Better DIPG Treatments

Researcher name: Prof Geraldine O'Neill

Institution: The Children’s Hospital at Westmead, AUS

Grant Name: Better Tools Investigator

Grant amount (AUD): Up to $223K

Grant Awarded: 2024

Status: Ongoing

Meet the Researcher

Prof Geraldine O’Neill is Head of the Children’s Cancer Research Unit (CCRU), the research-dedicated arm of the Cancer Centre for Children at the Children’s Hospital at Westmead, and Conjoint Professor with the University of Sydney. Her pioneering research has defined how cancer cells interact with their surrounding tissue environment. Her lab is particularly focused on developing advanced pre-clinical models for brain cancer, leveraging cutting-edge techniques in tissue engineering, cell biology, and biophysics to enhance treatment options for patients. Prof. O’Neill is deeply committed to translating scientific discoveries into new clinical therapies. As the head of the CCRU, her mission is to transform childhood cancer into a thing of the past.

Children diagnosed with DIPG, the most lethal childhood brain cancer, currently have no effective treatments. Despite hearing about promising treatments resulting from laboratory research, these often fail in real patients because our evaluation tests aren’t informative and stringent enough. Prof O’Neill’s project aims to develop better tests by using lab-grown brain structures and patient-derived cancer cells. This improved pre-clinical DIPG model will provide a more accurate picture of how treatments will perform in real patients.

This project is game-changing because it uses lab-grown brain structures and patient-derived cancer cells to provide a more accurate assessment of treatment effectiveness for DIPG. Traditional tests often exclude healthy brain cells, which are crucial in understanding treatment responses. This new method has already revealed that some therapies, which seemed promising in standard tests, may not be as effective in real patients. This approach offers a more realistic and rigorous evaluation platform for potential DIPG treatments, potentially leading to better treatment strategies.

This project can potentially help people with brain cancer by using an improved DIPG model to evaluate new immune cell therapies. By doing so, this will provide a more accurate of how these therapies will perform in real patients. This project aims to broaden the range of available and effective treatments, increasing the chances of finding a cure for every child with brain cancer.

This project aims to develop better preclinical models for pediatric high-grade gliomas (pHGGs), which includes DIPG, by incorporating human stem cell-derived brain organoids and DIPG patient-derived tumouroids. These advanced models will enable more precise testing of new immune cell therapies. The O’Neill lab will utilize this sophisticated DIPG model to evaluate novel CAR T-cell therapies targeting EphA2, which is present in a significant number of pHGG cases, and TCR T-cell therapies targeting PRAME, an antigen over-expressed in various cancers. This project will use liquid biopsies to monitor the effectiveness of these therapies by detecting cell-free DNA, therefore providing a biomarker of intra-tumoural CAR T-cell activity.

The overarching aims in this grant includes:

Aim 1. Assess PRAME TCR T alone and in combination with EphA2 CAR in pHGG. The O’Neill lab aim to address tumour-associated antigen heterogeneity that confounds CAR T treatment of solid tumours and find treatments targeting multiple antigens.

Aim 2. Develop in vitro assays to track T-cell treatment efficacy precisely and accurately in patients. The O’Neill lab’s goal is to develop assays that will use minimally invasive blood/cerebrospinal fluid sampling of cell-free DNA to monitor therapy response and ensure that the observed responses are directly linked to the effectiveness of the CAR T-cell treatment.