Targeting the inflammatory GM-CSF pathway in high risk CMML
Ravindra Majeti
PhD, MDStanford
Project Term: November 1, 2023 - October 31, 2028
Chronic myelomonocytic leukemia (CMML) is a rare but poorly understood blood cancer often presenting with crippling inflammatory symptoms that frequently evolves into acute leukemia. In an ongoing clinical trial, we have compelling molecular and clinical data that this disease responds effectively to blockade of GM-CSF with lenzulimab, a well-tolerated and safe antibody, in combination with azacitidine. Here, we propose an integrated research program to investigate targeting of the GM-CSF pathway in high risk CMML using our carefully matched patient samples, proprietary GM-CSF tools, and humanized in vivo CMML models.
Chronic myelomonocytic leukemia (CMML) is a rare but poorly understood blood cancer often presenting with crippling inflammatory symptoms that frequently evolves into acute leukemia. In an ongoing clinical trial, we have compelling molecular and clinical data that this disease responds effectively to blockade of GM-CSF with lenzulimab, a well-tolerated and safe antibody, in combination with azacitidine. These results have led us to hypothesize that CMML is an inflammatory cancer driven by targetable cytokines, particularly GM-CSF, acting on mutated monocyte precursor and/or progenitor cells. Moreover, we predict that early intervention directed at monocyte cytokine signaling will delay the onset of acute leukemia, improve quality of life, and reduce autoimmune complications. Here, we propose to investigate these hypotheses through an integrated program of 3 distinct projects and 2 cores focused on translational studies of patient samples from the lenzulimab clinical trial, studies of aberrant cytokine signaling in CMML, and investigation of the CMML stem cell compartment and characterization of pre-clinical human CMML models.