Cytokines and T Cell Development

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

We previously showed that the IL-7 receptor pathway drives acute lymphoblastic leukemia (ALL) the most common cancer in children. We have studied this in two ways: 1) investigation of the interaction of this pathways with others, suggesting combination drug treatments and 2) development of a novel anti-IL-7R monoclonal antibody to treat patients with ALL. We show that mutations in IL-7R creates an oncogene that is necessary but insufficient to drive leukemia in a mouse model. Combining this oncogene with several other oncogenes found in patients has demonstrated cooperating partners in generating aggressive leukemia. The first cooperating partner we identified was Ras and showed that drugs acting in this pathway cooperated with a drug targeting the IL-7R pathway showed anti-leukemic effects in vivo in mice. More recently we found that RasGRP1, a Ras activator that is frequently overexpressed in ALL also induced aggressive leukemia when combined with mutant IL-7R. We next found that overexpression of cMyc cooperated with mutant IL-7R and the resulting leukemia responded to drugs targeting the Myc pathway together with a drug targeting the IL-7R pathway. Most recently we showed that TLX3, which is frequently activated by translocation in ALL, cooperates in inducing a multiphenotypic leukemia and responds to drugs targeting this pathway. Because IL-7R is expressed on the cell surface of a majority of ALL cells we reasoned it could respond to anti-IL-7R monoclonal antibody. We generated a novel antibody in mice and chimerized it with human Ig constant regions. This we showed was highly effective in a number of human ALL lines in mice. The antibody was patented and licensed and a company was created to develop a clinical trial in relapsed patients. Substantial funding was raised from public and private sources to support the trial. A toxicity trial in macaques was successfully completed last month and an application to FDA for an investigational new drug was completed last week. We are organizing a multicenter clinical trial to initiate in coming months