Natural Killer cells as critical part of the tumor microenvironment in predicting, regulating, and targeting Smoldering Multiple Myeloma progression to overt Multiple Myeloma

• Applicant: Dr. Rosa Toenges
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506621199

Multiple myeloma (MM) is a clonal plasma cell disorder that accounts for approximately 10% of all hematologic cancers. MM almost always progresses from the precursor states of monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), indicating multistep evolution of tumor cells from the original stages of tumor development to symptomatic disease. Studies indicate that MGUS/SMM clones already harbor the cytogenetic and molecular genetic variants seen in MM. However, not all patients with MGUS/SMM will develop MM, suggesting that further tumor evolution may critically depend on the surrounding cells in the microenvironment that can create conditions permissive for or against clonal expansion. Early intervention represents an attractive treatment option. Therefore, it is imperative to identify the clinically significant microenvironmental alterations that promote progression and develop targeted therapies to reinstall a functional anti-tumor immunosurveillance.Accumulating evidence demonstrates the important role of natural killer (NK) cells in controlling MM as part of the innate immunosurveillance. The Ghobrial laboratory (host institution) generated single-cell RNA sequencing data of the MGUS/SMM microenvironment demonstrating that tumor-permissive immune dysregulation may be established as early as in the MGUS stage, with a progressive increase of NK cells accompanied by a NK cell phenotype shift. A detailed and comprehensive molecular characterization is essential to precisely define the role of NK cells as either bystanders or protagonists actively contributing to disease progression in MM. Harnessing the immune system is a promising anticancer therapeutic strategy and immunotherapy may reverse some of the microenvironment changes occurring during the progression from SMM to MM. CAR-T cell (Chimeric antigen receptor) therapy shows promising results in MM patients with complete remission rate of 40 to 80%. However, serious toxicities, high relapse rates, and delayed treatment due to a long manufacturing process limit the therapeutic efficacy. NK CAR cells provide a potential strategy to produce ‘‘off the shelf’’ targeted allogeneic lymphocytes with improved antitumor efficacy suitable to treat MM. Our hypothesis is that the permissive immune microenvironment is a critical regulator of disease progression from SMM to overt MM, and defining these alterations is critical for the development of immunotherapeutic approaches that intercept disease progression. The proposed research will determine the role of NK cells as part of the tumor microenvironment and of the host immune response that can be enhanced by the use of NK CAR cells.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Irene M. Ghobrial