Preclinical study shows the targeted drug giritinib enhances the efficacy of CAR T cells in the treatment of two cases of childhood leukemia

A preclinical study shows that Gilteritinib (Brand name:

Both types of leukemia are characterized by abnormal levels or excessive activity of FLT3, a protein on the surface of some leukemia cells. Children with FLT3-mutant AML and infants with KMT2A-rearranged ALL urgently need new therapies to minimize toxicity and improve long-term remissions. Preclinical studies take a two-pronged approach, targeting leukemias expressing FLT3 by combining CAR T-cell immunotherapy and the FLT3 inhibitor Genitinib.

The researchers found that they achieved better destruction of leukemia cells in preclinical models of FLT3-mutant AML and KMT2A-rearranged ALL by combining a drug called tyrosine kinase inhibitor gireltinib with FLT3 CAR T-cell immunotherapy compared to using the two treatments separately. Initially, the team hypothesized that the improved outcomes were due to the combined effects of each different type of therapy targeting leukemia cells individually, but made a surprising discovery.

While we anticipate that these therapies will directly target leukemia, we also observed that giritinib directly increased CAR T cell numbers, improved eradication of leukemia cells, and provided enhanced and sustained anti-leukemia activity. CAR T-cell therapy centers on the patient's own T cells, which are part of the normal immune system and can be collected from the patient's blood and engineered in the lab to recognize specific proteins on the surface of cancer cells. The engineered CAR-T cells are then multiplied and returned to the patient, where they attach to and kill leukemia cells.

In preclinical studies, CAR-T cells targetingFLT3 were previously developed and shown to be effective against these types of leukemia. FLT3 contains activating mutations in 20-30% of pediatric AML patients and is abnormally highly expressed in KMT2A-rearranged ALL. Most infants younger than 12 months with ALL have KMT2A-rearranged leukemia and have a poor prognosis, with long-term survival rates below 60%.

Genitinib is a targeted small molecule drug that prevents leukemia cell survival and proliferation by inhibiting the signaling of multiple receptor tyrosine kinases, including FLT3. It has been approved by the U.S. Food and Drug Administration for the treatment of adult patients with relapsed or drug-resistant FLT3-mutated AML.

Combination therapy with geritinib may also enhance the efficacy of alternative leukemias targeting CAR T-cell products, highlighting the potential of geritinib to enhance the effectiveness of other CAR T-cell immunotherapies already in clinical use in pediatric patients.

References:https://www.roswellpark.org/newsroom/202412-preclinical-study-shows-targeted-drug-strengthens-power-car-t-cell-therapy-two