A team of Children’s Medical Research Institute (CMRI) scientists has identified a new method for producing a therapeutic product that has the potential to improve the treatment of cancer.
The work by Associate Professor Leszek Lisowski and his Translational Vectorology Research Unit is published in the journal Molecular Therapy today.
Chimeric antigen receptor (CAR) T cells, also known as CAR T therapies, are a relatively new form of treatment showing very exciting results for several types of cancer. While initially validated for the treatment of B cell malignancies, especially acute lymphoblastic leukaemia (ALL), the technology has also shown promise for other cancer types, including solid tumours.
In most cases, CAR T cells are made by modifying the patients’ own T cells so they produce a specifically designed chimeric antigen receptor, enabling them to seek and kill cancer cells. To convert T cells into CAR T cells, the patients’ cells are modified using a viral vector encoding the CAR component.
Currently, there are six US Food and Drug Administration-approved CAR T products, all of which use viral vectors as a delivery system. To improve CAR T products, researchers are investigating how the viral vectors affect CAR T cells, especially their specificity and long-term efficacy. In recent years, advances in CAR T technology have included the use of new viral vectors to deliver the functional CAR to patients’ T cells to generate therapeutic CAR T products. Based on their inherent safety, AAV vectors, which are most commonly used to deliver therapeutic genes directly to patients and are currently the technology behind eight marketed gene therapy products, are the next frontier in CAR T products.
In this study, Associate Professor Lisowski and his team, including author Adrian Westhaus, developed a new method to bioengineer novel bespoke AAV variants that enable more efficient targeting of patients’ T cells, positioning them as the next generation of AAV vectors for CAR T product development.
In a proof-of-concept study, the CMRI team has discovered two novel AAV capsids, known as AAV-T1 and AAV-T2, which can produce therapeutic CAR T cells using a five-fold lower dose of the vector. This significantly lower vector dose not only could lead to a lower cost of future CAR T products, but, more importantly, the team was also able to show that the therapeutic CAR T cells developed using these new AAVs killed cancer cells with higher efficiency, thus potentially also increasing the therapeutic potency of the new therapies.
“To achieve this goal, we studied how AAV vectors influence the rate of gene editing and have used that knowledge to develop a novel AAV selection method, which allows us to rapidly bioengineer novel AAVs for gene editing applications, which is the strategy used to permanently modify T cells to make CAR T cells,’’ A/Prof Lisowski said. “Following the selection process, we performed functional validations of the selected viral vectors. The two top performing candidates (AAV-T1 and AAV-T2) generated CAR T cells more efficiently and produced CAR Ts that were more functionally active than AAV6, which is the AAV currently used for CAR T development.’’
The CMRI authors on the paper were Adrian Westhaus, Elena Barba-Sarasua, Suzanne Scott, Maddison Knight, Santiago Mesa Mora, Ramon Roca-Pinilla and A/Prof Lisowski. They worked with collaborators in Australia and across the world including Yuyan Chen, Kenneth Hsu, Benjamin Houghton, Predag Kalajdzic, Geraldine O’Neill, Adrian Thrasher and Giorgia Santilli.
The full publication can be found here: https://www.cell.com/molecular...(24)00811-6.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1525001624008116%3Fshowall%3Dtrue