Catching Houdini - targeting TP53-deficient ALL

Abstract

With over 90% being cures, the treatment of acute lymphoblastic leukemia (ALL) in children is a success story. Improving this cure rate even more starts with the identification of those patients at risk and defining novel treatment strategies to combat specifically the type of tumor that these patients suffer from. This study focused on a rare subgroup of leukemia, characterized by mutations in the TP53 gene, which have a dismal prognosis when treated with standard of care protocols. Doctoral candidate Willem Cox found that tumor cells that have this mutations are intrinsically resistant to nearly all of the drugs that are used in the treatment, including novel antibody-drug-conjugates. Importantly, his study also showed that these tumor cells can be re-sensitized to treatment when specific drug combinations are used, for example when an HDAC inhibitor is added to the treatment. With novel cellular immunotherapies moving their way towards first and second-line treatment of ALL, Cox studied whether loss of TP53 changed the response to this type of treatment, called CAR T. Similar to the response to the chemotherapeutics, tumor cells with a defective TP53 gene are less responsive to CAR T treatment. Indeed, comparing the outcome of CAR T treatment in patients suffering for TP53 defective tumors to patients with a normal TP53 gene showed that CAR T treatment is ineffective against TP53 defective tumors. Cox was able to attribute this resistance to lower levels of so-called Death Receptors that are used in CAR T treatment to kill the tumor cells. These studies underscore that tumors characterized by a defect in the TP53 gene are notoriously difficult to treat because of cell intrinsic resistance to both conventional chemotherapeutics and novel immunotherapies. It is therefore important to search for TP53 mutations at diagnosis and later when second line treatments are needed. And although Cox showed that current therapy protocols are unsuccessful, his studies provide a proof of principle that cells can be sensitized to treatment by targeted combination treatments which aid in the design of better treatment for these patients.