Australian first: On-site vector production and use in a gene therapy trial

Results of a Phase I Clinical Trial which employed genetic engineering technologies developed in-house at Kids Research have been published in Human Gene Therapy.  It is the first example of a group in Australia to succeed in safely manufacturing and using clinical-grade vectors.

The research, initiated nearly twenty years ago by Dr Geoffrey McCowage, paediatric oncologist at Cancer Centre for Children at The Children’s Hospital at Westmead, was a collaborative effort from clinicians and research teams at the Children’s Cancer Research Unit (CCRU) and the Gene Therapy Research Unit (GTRU).

Dr Belinda Kramer of CCRU, together with Professor Ian Alexander of GTRU, led the design and development of the trial vector and protocol. 

Gene therapy is a technology that involves introducing a new or repaired version of a gene into the body. Once cells have been removed from the body, this can be done using a viral vector, which shuttles the desired gene into the cell’s DNA. The cells can then be reintroduced into the patient.

In this study, a transport vector was used to insert a gene encoding methyl-guanine methyl transferase (MGMT), a naturally-occurring protein that protects cells against the effects of various chemotherapeutic agents, into the bone marrow cells of children undergoing chemotherapy.

Normally, vectors are commercially sourced from overseas at great financial cost.  In an Australian first, this study built the capacity to make clinical-grade vectors on-site, using specialised cleanroom infrastructure provided by the Gene and Cell Medicine Facility at Kids Research.  

The challenge in making and using vectors lies not only in the complex manufacturing process, but in satisfying the rigorous regulatory process for approval for its use in a clinical trial.  The regulatory experience gained from this study is invaluable, and has set a foundation that will underpin future gene and cell therapy trials at Sydney Children’s Hospitals Network.

At the conclusion of the trial, although positive results had been reported in the adult patient group, results were not as anticipated for the paediatric patients.  Unfortunately, although bone marrow cells incorporated the introduced gene, it was difficult to obtain sustained engraftment of these cells to a level that could have led to a reduction in the side effects of treatment and to allow for dose escalation of chemotherapy.

Despite this result, the project has had other positive outcomes.   In establishing the capacity to develop vectors for gene therapy on site at The Children’s Hospital at Westmead, researchers and clinicians can react to the needs of patients more efficiently and at a substantially lower cost than if the vectors were commercially sourced.  This has facilitated the accelerated translation of innovative research from bench to bedside, and in therapeutic applications beyond cancer.

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

Using the Gene and Cell Medicine Facility and their significant expertise in the field, Dr Kramer’s team at the CCRU is now developing a new vector to be used to genetically modify T cells.  This would allow them to identify, bind to and kill solid tumour cells.  

This work would not have been possible without the generous funding of The Kids’ Cancer Project, Kids Cancer Alliance and the Sporting Chance Foundation.