For the past 20 years, our Institute has been testing potential new leukaemia treatments to help fast-track the best into clinical trials. Here, we reflect on our experiences and successes.
How we are helping kids with leukaemia
For many years, a strong focus of the Institute’s research has been on improving the outlook for kids with acute lymphoblastic leukaemia (ALL), the most common cancer diagnosed in children. Our research has had a significant impact on survival rates, particularly in those with high-risk disease.
One of the most important tools enabling our leukaemia research — a critical component of our success, in fact — has been our laboratory model of ALL, widely recognised as the best in the world.
Professor Richard Lock, Head of our Leukaemia Biology Group, explains: “Our living model, based on specially bred mice growing human leukaemia cells, closely mimics the disease in children. This makes it possible to carry out meaningful experimental work without involving children."
So useful is our model, it led to our Leukaemia Biology Group being selected as the only non-US based research team to be part of a National Cancer Institutes-funded initiative known as the Pediatric Preclinical In Vivo Testing Program (PIVOT; originally known as the PPTP and then PPTC), which has now been running for two decades.
Recently, a review summarising the 20-year results of this important initiative was published in the high-impact journal, Pharmacology & Therapeutics. [https://doi.org/10.1016/j.pharmthera.2024.108742]
The importance of PIVOT
Before a potential new treatment can be tested in children, it needs to undergo extensive testing in the lab. Known as preclinical testing, this takes time — often several years. The goal of the PIVOT program is to accelerate the testing and approval of new childhood cancer treatment drugs by identifying the most promising candidates, so these can be fast-tracked into clinical trials.
“For the last 20 years, we’ve carried out all of the leukaemia testing for the PIVOT program,” says Professor Lock. “Being invited to join this consortium in the early 2000s was a tremendous honour for me personally, and justification for the Institute’s support of my fledgling research group as I made the difficult transition in my career from the USA to Australia.”
Our model of ALL
The main type of model used by Professor Lock and his team is known as a patient-derived xenograft, or PDX. This is based on laboratory-bred mice that are growing human cancer cells; that is, cells that have been taken directly from patients with cancer.
Each individual mouse grows one individual patient’s cells; so, to all intents and purposes, the mouse has that child’s disease. This provides an unparalleled opportunity to see how the child’s cancer responds to different drugs in vivo (inside the living body).
“By testing potential new treatments in our living model, we can make sure that only safe and effective drugs proceed to testing in children, and we can prioritise those drugs that our tests show are the very best candidates,” explains Professor Lock.
Results of testing
Professor Lock’s team has been evaluating new drugs and drug combinations each year since 2005, with close to 100 novel drugs tested during that time. Several of these have been progressed to clinical trials as a result of the team’s results.
New drugs progressed to clinical trials include a novel prodrug called OBI-3424, which is currently being tested in an ongoing phase II clinical trial in relapsed and refractory T-cell ALL, open at more than 100 centres in the USA. The team also led the preclinical development of a drug known as VTP-50469 (revumenib) that has now progressed to five clinical trials in the USA, Europe and Australia. Initial results have been exciting, with a remarkable 63% overall response rate in patients with advanced acute leukaemia, both adults and children, in whom standard treatment had failed.
Looking to the future
Our Institute continues to test several new drug candidates for leukaemia each year through the PIVOT program, and Professor Lock has high hopes for the future.
“I’d like to be responsible for the rapid transition of more novel drugs into clinical trials in children and adults with leukaemia,” he shares. “We all want to see new treatments become available that improve not only the likelihood of survival but also quality of life, without the toxic side-effects of conventional treatment.”
