Dr. Lee on the Mechanism of Action of Cirmtuzumab in MCL or CLL

Hun Ju Lee, MD, an associate professor of medicine in the Department of Lymphoma & Myeloma and the Jessica and Jeffrey Brue Endowed Professor of Lymphoma Research at The University of Texas MD Anderson Cancer Center, discusses the mechanism of action of the investigational ROR1 inhibitor cirmtuzumab in combination in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).

ROR1 is an onco-embryonic tyrosine kinase receptor that is re-expressed at high levels on many hematologic and solid cancers, although this is not the case with regard to normal adult tissues. ROR1 binds Wnt5a, which leads to increased tumor growth and survival. The humanized monoclonal antibody cirmtuzumab was developed to inhibit the tumor-promoting activity of ROR1.

In a phase 1/2 trial, cirmtuzumab was examined in combination with ibrutinib (Imbruvica) in patients with MCL or CLL; the drugs were combined in an attempt to increase the signaling in the ROR1 pathway, says Lee. Lymphoma and leukemia cells are very intelligent, explains Lee, thus they are able to take advantage of alternative sources of growth signal when BTK is blocked.

Results from preclinical studies demonstrated that patients with high levels of ROR1 had lower survival rates. Investigators believe that this could be one of the main contributing factors to the development of resistance to BTK inhibition in lymphoma and leukemia cells, concludes Lee.