Scientists have developed a modified immunotherapy that achieved complete remission in mouse models of high-risk childhood acute lymphoblastic leukemia, potentially offering new hope for patients with limited treatment options. The research, published in Blood, demonstrates that CAR-iNKT therapy targeting two cancer markers simultaneously outperforms current standard treatments.
Dual-Target Approach Shows Superior Efficacy
The research team, led by Professor Anastasios Karadimitris at Imperial College London and Professors Anindita Roy and Thomas Milne at the University of Oxford, engineered CAR-iNKT cells to recognize both CD19 and CD133 markers on high-risk leukemia cells. This dual-target strategy proved highly effective in preclinical testing, with 100% of treated mice surviving and remaining cancer-free long after treatment.
"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 leukemia than with CAR-T," said Professor Karadimitris.
In direct comparisons, standard CAR-T therapy could only eliminate leukemia for a few weeks before the cancer returned, while CAR-iNKT therapy maintained complete remission throughout the follow-up period.
Addressing Critical Treatment Gaps
High-risk acute lymphoblastic leukemia, the most common cancer in children, presents significant therapeutic challenges. While approximately 80% of children with standard-risk forms achieve cure, high-risk variants occurring in infants and children have cure rates of only around 50%.
The new therapy addresses a critical limitation of current treatments by effectively targeting leukemia cells that have invaded the space around the brain and its lining, called meninges. This capability is particularly significant since cancer remaining in this area is one of the primary reasons for relapse in high-risk childhood leukemia.
"CAR-T therapy is effective in treating some cases of high-risk leukemia in children but there is still a chance of the cancer coming back in around one third of patients," Professor Karadimitris explained. "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."
Off-the-Shelf Advantage
Unlike standard CAR-T therapy, which requires weeks to engineer a patient's own immune cells, CAR-iNKT therapy uses invariant natural killer cells (iNKT cells) that can be manufactured from healthy donors and stored in advance. This "off-the-shelf" approach enables immediate treatment availability, which is crucial for rapidly progressing high-risk leukemia cases.
The therapy demonstrated effectiveness across multiple challenging sites, completely eliminating cancer cells from bone marrow, spleen, and the central nervous system. Importantly, safety testing in mice engineered to produce human blood cells showed that the therapy did not interfere with normal blood cell production, despite targeting CD133, which is also present on healthy blood cells.
Clinical Translation Pathway
Dr. Natalina Elliott, co-first author from the University of Oxford's Department of Paediatrics, emphasized the therapy's potential: "We have found that targeting two markers on the leukemia cells using CAR-iNKT therapy is more efficient at clearing cancer cells in mice than with CAR-T, even when it has spread to the brain. Reassuringly, we also did not find evidence of major toxicity in our preclinical models even when using high doses of the CAR-iNKT cells."
The research team is now working toward clinical translation, with Dr. Hongwei Ren noting: "This is the promising first stage in developing a more robust treatment for this form of leukemia 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."
Professor Roy highlighted the urgent need addressed by this research: "Cure rates for high-risk infant and childhood leukemia lag behind standard risk childhood leukemia. There is an urgent need to develop more effective treatments for this vulnerable patient population in order to prevent relapse."
The work was funded by Cancer Research UK and Children with Cancer UK, with the team receiving a Children and Young People's Cancer Innovation award in 2021 to develop this novel immunotherapy approach.
