The latest on CAR T-cell therapy research
A clinical trial will test advancements in chimeric antigen receptor (CAR) T-cell therapy developed in Australia and funded by the Leukaemia Foundation*.
The clinical trial opened in Sydney in August 2017 for people with relapsed B-cell leukaemias and lymphomas, following TGA and ethics approvals.
CAR T-cells are a revolutionary form of treatment for B-cell malignancies. In people with previously incurable disease, across multiple clinical trials, T-cells have resulted in complete response (CR) rates of approximately 80% against B-cell acute lymphoblastic leukaemia (ALL), and 50% CR rates against chronic lymphocytic leukaemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL).
Yet access to this therapy is limited due to the cost and complexity of CAR T-cell generation.
Dr David Bishop, who is completing his PhD, funded by the Leukaemia Foundation’s National Research Program*, is investigating new methods of generating CAR T-cells to address these issues.
Leukaemias and lymphomas that arise from a subset of white blood cells called B-cells are among the most common forms of blood cancer.
Standard treatment for these conditions involves chemotherapy and rituximab, an antibody that specifically targets and destroys B-cells, as well as bone marrow transplants for those people who relapse or are high risk.
“Unfortunately, despite these treatment options, a subset of patients with highly aggressive leukaemia or lymphoma will have incurable disease,” said Dr Bishop.
In recent years, a ground-breaking new form of treatment for B-cell malignancies has been developed – CAR T-cell therapy.
“The normal role of a T-cell is to provide immunity against foreign invading pathogens, like bacteria and viruses. Because cancer cells arise from normal body tissue, naturally occurring T-cells have difficulty recognising them as abnormal,” Dr Bishop said.
“To overcome this problem, a synthetic CAR can be introduced into a naturally occurring T-cell by genetic modification, which enables it to recognise markers on the surface of B-cell leukaemias and lymphomas, and destroy them.
However, patients can only access CAR T-cells in clinical trials run in only a small number of centres worldwide.
“Factors contributing to this situation include the cost and complexity of CAR T-cell generation. My research has investigated new methods of generating CAR T-cells to address these issues, and also to improve CAR T-cell safety,” said Dr Bishop.
“We have developed a process that essentially cuts the CAR gene from a DNA template and pastes it into the T-cell genome.
“This has enabled us to reduce the cost of CAR T-cell production by 10-fold, to approximately US$10,000 per patient.
“We expect to open a clinical trial of these CAR T-cells at Westmead Hospital later in the year, for the treatment of patients with relapsed or refractory B-cell malignancies following allogeneic bone marrow transplant.”
Dr Bishop said another factor contributing to the cost of CAR T-cell therapy was the current need for every patient to have an individualised product, generated from their own T-cells.
“The main reason for this is to avoid graft-versus-host disease that could occur if CAR T-cells were generated from donor T-cells.
Because CAR T-cells, like any treatment, may have unwanted side-effects, Dr Bishop said it would be useful to be able to selectively eliminate them in the event of unacceptable toxicity.
“My research has explored incorporating a ‘suicide gene’ into CAR T-cells that sensitises them to the drug rituximab,” he said.
“When exposed to this drug, virtually all CAR T-cells expressing the suicide gene are eliminated, but ordinary T-cells are left untouched.
Dr Bishop said the CAR T-cell field was rapidly progressing globally.
“It is an incredibly exciting area of research to be involved in, and it’s very satisfying to see your ideas progress from a pre-clinical setting to being translated to the clinic where they can potentially have a meaningful impact on patient care.
“With a PhD scholarship, the Leukaemia Foundation has enabled me to take the first steps towards that goal by providing funding to undertake high quality research and share my findings with the world at international conferences,” said Dr Bishop.
* Dr Bishop has a Leukaemia Foundation PhD Scholarship (Clinical) supported by the NSW Community Foundation, N&P Pinter, of $60,000 per year from 2014-2017 (Immune cell therapies for lymphoma, leukaemia and post-transplant viral infections).