Targeting MS4A3 to Treat Chronic Myelomonocytic Leukemia (CMML)
Abstract
Scientific Objective: In this project we hypothesize that targeting MS4A3, a protein that uniquely distinguishes chronic myelomonocytic leukemia (CMML) stem cells from normal stem cells found in blood and bone marrow, is selectively toxic to CMML leukemia stem cells (LSCs). We propose that eliminating all MS4A3 expressing cells will eliminate the CMML clone while preserving the stem cells that will reconstitute the hematopoietic system with healthy blood cells. Instead of focusing on specific genetic mutations present in each individual patient, we hope to set the stage for a new standard of care using MS4A3 as an effective immunotherapy target for all CMML patients. To achieve our objectives, we will test whether MS4A3 separates between residual healthy stem cells and CMML stem cells. We will then generate antibodies and CAR T cells to target MS4A3. We expect clinically relevant outcomes within 12 months. Rationale: Patients with CMML have a very poor prognosis and many patients die within two years. Advances in molecular genetics have made great impacts on other myeloid malignancies, but no impact on CMML management. One of the reasons for this is that CMML is a rare disease that can be difficult to diagnose, an impediment for systematic laboratory investigation and clinical trials. Another reason is that CMML can be caused by a variety of mutations, most of which cause a loss of protein function that cannot be targeted with drugs. Currently there is no standard of care therapy for CMML, and studies targeting molecular abnormalities have been unsuccessful. In contrast to prior research, we hypothesize that an immunotherapy approach aiming at MS4A3 as a unique feature common to CMML stem cells from all patients will be both effective and widely applicable. Importantly, MS4A3 also belongs to the same protein family as the B-lymphocyte antigen CD20, one of the most successful immunotherapy targets. Targeting CD20 using antibodies (rituximab) or chimeric antigen receptor (CAR) T cells has greatly improved survival of patients with CD20-positive blood cancers. We are targeting the MS4A3 as it is expressed in all CMML patients. Within the 12 months we will be able to test our hypothesis to the point where we can determine whether larger studies are justified to validate MS4A3 as a therapy target in pre-clinical models, and ultimately, clinical trials. This would be the first immunotherapy approach to treating CMML, a rare cancer that currently has extremely poor outcomes. Focus Area: This project targets the Fiscal Year 2021 Rare Cancers Research Program Focus Area: Therapy, as it aims to identify a novel therapeutic strategy for treating CMML, a rare cancer that affects 3-4 people out of every 1 million people in the U.S.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211073
Entities
People
- Michael Deininger
Organizations
- United States Army