Antibody drug conjugate may tackle drug-resistant ALL
A collaborative team has found a new way to treat acute lymphoblastic leukemia (ALL), the most common form of cancer among children.
The study, conducted by investigators from the University of Manchester in the UK, Tata Translational Cancer Center in India, the University of Zurich in Switzerland, and Pfizer Inc in the USA, has shown that the 5T4 oncofoetal glycoprotein on cell surface may be the cause of chemotherapy resistance in ALL, and that targeting 5T4 with an antibody drug conjugate called A1mcMMAF improved outcomes of mice engrafted with 5T4 positive patient derived xenograft cells.
ALL is most common in children younger than 5, although it can be also diagnosed in adults. The five-year survival rate for childhood ALL has been significantly improved over time and is now 90%. Treatment for the disease generally includes intensive chemotherapy, which may come with a long list of side effects, such as anemia, infection, bleeding, hair loss, and even an increased risk of developing a secondary cancer.
In this work, lead researcher Prof. Peter Stern and the team examined samples from children with ALL with low or high risk of relapse. It is well known that leukaemic cells that remain in patients after remission induction therapy are the major cause of relapse. So the number of leukaemic cells remaining can help predict outcome of childhood ALL. Those with larger numbers of leukaemic cells remaining tend to have inferior results.
The investigators found a high proportion of 5T4 positive leukaemia cells in patients with a high risk of relapse but not in children who responded well to initial treatment. Further investigation showed that 5T4 positive leukaemia cells are more clonogenic and preferentially localised to bone marrow, making it more difficult for chemotherapy drugs to kill them.
When the investigators used a 5T4-antibody drug conjugate, called A1mcMMAF, to treat mice engrafted with a 5T4 positive ALL cell line, the survival of the mice were greatly improved. Moreover, A1mcMMAF treatment did not cause toxic effects.
The study appears in the journal Haematologica.