Two steps forward in chemotherapy protection

30 June 2017

The ability to treat patients with highly toxic chemotherapy drugs without damaging healthy cells has posed a challenge for oncology staff for a long time.

Working collaboratively in our purpose-built Gene and Cellular Medicine Facility – one of the first in Australia – our internationally recognised gene therapists, molecular biologists and bio-informaticians successfully demonstrated in laboratory trials that it was possible to protect gene modified cells.

In a wonderful example of progressing life-saving research from the bench to the bedside, we discovered in a small animal model, that transfer of a mutant gene into specific stem cells, prior to delivery of a combined drug and small molecule inhibitor, allowed higher doses of chemo to be tolerated.  This innovative research clearly demonstrated that it was possible to protect gene-modified cells from the effects of chemotherapy.

Thanks to the tireless efforts of our discovery researchers these results unlocked the possibility that similarly using this mutant gene in a patient’s own cells, it may be possible to  protect their bone marrow from chemotherapy. Driven by the science and with a determination to find better treatments for children with brain tumours, Dr Belinda Kramer and her laboratory team in the Children’s Cancer Research Unit, and alongside clinical colleagues, has for the past 12 years been on this inquisitive mission.

“When we started work on this protocol we knew it was the first step along a difficult road. As with all science and innovative research, we proceeded with caution while remaining optimistic,” Belinda said.

We wanted to know if we could reduce off-target toxicity, in other words protect the healthy cells in the bone marrow being targeted with chemotherapy. If this was possible, we could then determine if dose escalation could possibly achieve greater therapeutic benefit of the chemotherapy against the tumour.

The need for a clinical trial was evident.

Access to clinical trials with large numbers of participants, provides patients with opportunities to take advantage of ‘leading edge’ treatments. However, unlike conducting clinical trials in the adult population, such trials in the paediatric setting continue to pose significant challenges due to relatively small numbers of available participants. Access to sufficient patient data to assess new treatments in large multi-site international clinical trials is problematic. Globally, this dilemma of small numbers for many childhood cancers has been addressed by the formation of international childhood cancer networks.

Our clinical trial was one involving a small number of cancer patients with brain tumours – all having exhausted all other conventional treatment options and who had a very poor prognosis. It aimed to test a vector, purposefully designed by our gene therapy team to confer drug resistance to chemotherapy agents.

The aim of this Phase 1 trial was to establish the safety and the feasibility of the gene therapy protocol and its potential long-term benefits for other paediatric conditions involving bone marrow.

At the conclusion of the trial, although positive results had been reported in the adult patient group, results were not as we anticipated for the paediatric patients.

Although we were able to safely manufacture and re-infuse gene modified cells into this group of patients, we conclude that conferring chemo-protection to allow for dose escalation to target a tumour would require additional testing of alternative protocols to that used in the study.

Despite disappointment, the breadth of work undertaken has confirmed that this protocol is incredibly complex and that any future trials of a chemo-protection strategy in this paediatric setting would need to include capacity for multi-centre enrolment.

What is inspiring however is that the information gained throughout the trial has established a foundation that will underpin future gene and cell therapy trials at The Children’s Hospital at Westmead. Data has been obtained that can be used to support future applications to the regulators to approve alternative protocols.

Valuable experience in the conduct of the trial is now being used to inform and advance a new immunotherapy trial for paediatric cancer patients with solid tumours who have relapsed after initial treatment.

This has largely involved returning to the laboratory, to perform pre-clinical experiments in tissue culture, and then once again in small animal models.

This immunotherapy involves genetically modifying T cells with a Chimeric Antigen Receptor (CAR) signalling protein that seeks out, binds to an antigen on the tumour and kills the tumour cells. This is critical in the treatment of a cancer that before diagnosis has spread (metastasised) from its primary origin.

The team is already collaborating with other international researchers in the field who have supplied the reagents to be used in the laboratory over the next 12 months to advance and test mouse models.

As the gene therapy vector constructed for the last clinical trial showed no negative consequences, our CCRU scientists will make refinements and develop a gene therapy – CAR T cell vector to allow targeting of solid tumour antigens.

Because of our proven success with clinical grade vector manufacturer, unlike many groups endeavouring to undertake Phase 1 studies internationally, we are able to manufacture within our own institution, at substantial cost savings and gain approval for its use from the Therapeutic Goods Administration via the Clinical Trial Exemption (CTX) Scheme.

Again we proceed with caution while taking another optimistic step forward in the search for better treatments for children diagnosed with solid tumours.

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