A new immunotherapy approach to cancer, known as Chimeric Antigen Receptor (CAR) T cell therapy, will likely revolutionise leukaemia treatment.
This approach is the most therapeutic advance in acute lymphoblastic leukaemia for generations, and might represent the beginning of a new era of engineered T cells for cancer therapy.
As Principal Hospital Scientist at the Blood and Marrow Transplant Research Laboratory at Sydney Children’s Hospital, Dr Alla Dolnikov has been working to develop a local CAR-T cell therapy program that includes a series of clinical trials administering this therapy to patients with leukaemia and lymphoma.
Working with investigators at the Sydney Children’s Hospital, including Associate Professor Tracey O’Brien and Dr Kenneth Micklethwaite from Westmead Institute for Medical Research, Dr Dolnikov says the technologies developed in this program will be potentially applicable to other tumours.
The primary advantage of CAR-T cell therapy is an increase in remission and survival of patients who had failed earlier treatments with other methods. CAR-T cell therapy has great potential to cure leukaemias and lymphomas, however it is not a widespread application yet.
The use of a novel, inexpensive, transposon-based system of CAR delivery to patient’s T cells, as a simplified alternative to presently used viral delivery, will enable cost-effective treatment of children and adults with leukaemia and lymphomas in Australia.
Perhaps more importantly, the work Dr Dolnikov is doing is intended to make such treatment, which has proven to be particularly effective in fighting childhood cancers, more openly available.
"CAR-T cell therapy is using the patient’s own immune cells, genetically modified in a laboratory with chimeric antigen receptor (CAR) that targets tumour cells,” Dr Dolnikov explained.
“When CAR-T cells are infused back to the patient’s circulation, they recognise cancer cells and kill them, and they do so very efficiently,” she said.
For over 25 years, Dr Dolnikov says, researchers have been working on this idea. In the last few years that work has been paying off, with “remarkable results” achieved in clinical testing.
"We’ve seen a response rate up to 90 per cent for certain types of leukaemia and lymphoma,” she said. “It has been particularly effective in the paediatric cohort, in kids with leukaemia and lymphoma.”
So far the clinical testing has been run on patients who have no other option. Chemotherapy, radiation and other treatments have not had an effect.
The approach developed by Dr Dolnikov and her collaborator Dr Micklethwaite, she believes, will result in a treatment that will cost only a fraction of the amount currently being charged – which is up to half a million dollars.
The therapy, she stresses, is not a cure-all for all cancer patients. When it does induce remission, the disease has returned in about 40 per cent of cases. That is why her new research project, paid for in part through a renewal of funding by The Kids’ Cancer Project, is so important.
Along with her research team, Dr Dolnikov is synthesising various combinations of treatments and genetic modifications in order to improve the remission rate. This involves the use of a drug called azacytidine (AZA) that is already included in standard care for patients with some forms of leukaemia, meaning there is no need to overcome any complicated and time-consuming regulatory hurdles before it is permitted to enter clinical trials.
AZA up-regulates multiple immune molecules in leukaemia cells and potentiates CAR-T cells. Significant variability in responses to AZA was observed between individual patients.
Continued funding from The Kids’ Cancer Project will be used to establish the association between AZA-induced immune signature and the outcomes of CAR-T cell therapy combined with AZA. That will be examined using the unique “humanised” mouse models.
"What we are suggesting is that if we pre-prime or pre-condition patients with this drug, it makes their leukaemia more sensitive to CAR-T cell therapy,” Dr Dolnikov said.
“Currently we are trying to find out which patients will respond better than others to make this therapy most effective. We’re hoping we can make it more broadly available very soon.”
"I hope strongly that one day CAR-T cell therapy for cancer will become part of the standard care for kids. And maybe one day it might even replace chemotherapy.”
“I don’t like it when people talk about chemotherapy, which induces an 85 per cent remission rate in kids, as ‘damaging’. Yes, it does some damage, but a few decades ago, when kids were diagnosed with leukaemia, there was little chance of survival. Now, 85 per cent of kids are induced into five-year remission, or cure by chemotherapy. But yes, there will be other, more gentle options in the future.”
As mentioned, some of these options are available now for children in Australia who have exhausted all other treatments, but they come at a high cost.
Dr Dolnikov’s work is intended to make such treatment more affordable and efficient. In fact, she said it should be a process that will be able to be carried out locally in hospitals across Australia, and that treatment will be delivered within two weeks of a patient being accepted.
"We still have to do a lot of hard work to make it really available for Australian patients,” Dr Dolnikov said. “That’s our end goal at the moment.”
The exciting news is that Dr Dolnikov, who has been working in cancer research for more than a quarter of a century, senses she is very close to her end goal. Ever since arriving in Australia in 1990, after leaving the chaos of her Russian homeland during its ‘Perestroika’ period of mostly failed political and economic reconstruction, she has been deeply involved in leukaemia research.
Now an Australian citizen and with four grandchildren (“…and I mustn’t forget to mention my poodle!”), she appreciates the vital importance of delivering results around childhood cancer.
"I’m very proud to say that the future is happening right now, with some of this amazing therapy available for some kids in Australia,” Dr Dolnikov said. “Our work is now aimed at making it available for all who need it.”