Scientists found that using two targets in CAR-iNKT therapy in mice can outperform standard treatments for high-risk childhood leukaemia.
Acute lymphoblastic leukaemia is a type of blood cancer and the most common cancer in children overall. While 80% of children receive treatment successfully and are cured, some forms are harder to treat. One of the most challenging cancers is high-risk leukaemia which occurs in infants and children and can only be cured around 50% of the time. One of the treatments used for these high-risk cancers typically use a therapy called CAR-T immunotherapy.
In a new study published in the journal Blood, researchers at Imperial College London, University of Oxford and University of Glasgow used a different version of immunotherapy called CAR-iNKT instead of the standard CAR-T immunotherapy. Scientists found that CAR-iNKT equipped to engage two markers together on the high-risk leukaemia cells called CD19 and CD133, completely cured the leukaemia in mice. They also showed this two-target approach was more effective than the one target approach, and while CAR-iNKT removed all leukaemia from mice and the animals remained free of leukaemia long after follow up, CAR-T could do this only for a few weeks, before the leukaemia returned. CAR-iNKT was also able to remove leukaemia cells that had invaded the space around the brain and its lining called meninges.
What we have found is that if you target two markers instead of the one marker using CAR-iNKT therapy, you have a greater chance of killing the cancer cells in mice with this type of high-risk leukaemia than with CAR-T." Professor Anastasios Karadimitris Department of Immunology and Inflammation
Standard CAR-T therapy uses a person’s own immune cells which are then engineered in a lab to fight cancer cells. This means the treatment is highly personalised but can take weeks to engineer. The modified therapy in this research used a different type of cell called invariant natural killer cells (iNKT cells) which are ready to use and can be used quickly when needed.
Professor Anastasios Karadimitris, lead author said: “CAR-T therapy is effective in treating some cases of high-risk leukaemia in children but there is still a chance of the cancer coming back in around one third of patients. There is a need to develop more powerful therapeutics to ensure that once the cancer cells are targeted and killed, they don’t make a resurgence.”
“What we have found is that if you target two markers instead of the one marker using CAR-iNKT therapy, you have a greater chance of killing the cancer cells in mice with this type of high-risk leukaemia than with CAR-T.”
Mice to model blood cancer
In current blood cancer treatment, CD19 is the marker used to target cancers. Scientists in this study analysed cells from patients to find two markers - CD19 and CD133 which were expressed in high-risk leukaemia cells.
The scientists then created a very faithful model of this type of blood cancer using human cells and then used CAR-iNKT therapy to kill these cancer cells in mice. They found not only was the therapy highly effective in treating the mice, with 100% of the mice surviving the treatment - it also killed cancer cells from the bone marrow, the spleen and from the space around the brain. One of the reasons for relapse from high-risk leukaemia in children is that blood cancer can remain in the space around the brain and therefore this may indicate a possible treatment to ensure that children are kept cancer free for longer.
CD133 is also found on the surface on human blood cells and so to test whether using this target could interfere with the human body’s ability to make normal blood cells, researchers also generated mice which had the ability to make human blood. They then used the therapy and found that the ability to make normal blood cells was not altered.
Implications for using CAR-iNKT therapy
Currently CAR-T therapy requires time to engineer a person’s own cells to be transferred back into them to treat cancer. The iNKT cells used in this study can be manufactured and stored well in advance to have them ready when required and can be created from any healthy cell donor.
Rapid treatment times can be especially important in high-risk leukaemia in children where the cancer can be rapidly progressing. The researchers are now hoping to develop a therapy in the future that can be used in humans, working in close collaboration with experts to bring this into clinical practice.
Dr Hongwei Ren, co-author said” “This is the promising first stage in developing a more robust treatment for this form of leukaemia seen in infants and children and we are excited to see that it has been successful in mice. We now need further work and funding to test the efficacy in clinical trials.”
This work was funded by Cancer Research UK and Children with Cancer.
The full paper is published in the journal Blood: ‘Off-the-shelf’ dual CAR-iNKT cell immunotherapy eradicates medullary and leptomeningeal high risk KMT2A-rearranged leukemia
