AG Nolting & Bisht-Feldmann
Our research group is embedded in multi-disciplinary network within the biomedical institues at the University Hospital in Bonn. Our translational research focuses on the tumor immunology of multiple myeloma (MM), particularly on the interaction of our immune system with MM cells in the bone marrow niche and in the context of minimal residual disease (MRD).
Multiple Myeloma and the Bone Marrow Microenvironment
Multiple myeloma is characterized by the accumulation of MM cells in the immune competent bone marrow (BM). The BM microenvironment contains specific niches that are highly specialized in providing essentiell cell–cell interactions and signalling molecules for the development and survival of many blood cell types. We learned that these interactions are also critical for the progression of haematological malignancies, such as multiple myeloma. In this regard, MM cells are believed to ‘hijack’ the normal hematopoietic BM niche to aid the extensive growth and proliferation of MM cells, and it was also shown that the multiple myeloma BM niche confers chemoresistance.
In this regard, we are very much interested in the analysis of the endostal hypoxic hematopoetic BM niche that provides an immune privileged suppressive site, triggered by FOXP3+ regulatory T cells (Tregs). This notion was further supported by the observation that large numbers of functional Tregs accumulate within the BM niche. So, Tregs might participate in creating a localized zone within the endostal hypoxic BM niche where MM cells are able to persist despite ongoing treament and evade our technical means currently available for MRD evaluation.
In addition to ongoing resarch regarding cell intrinsic capacities for clonal expansion of resistant MM cells, it is of our great interest to analyze the bone marrow microenvironment, since it has been shown to propagate survival and chemoresistance of MM cells, and it is reasonable to suggest that both intrinsic and extrinsic MM cell factors act in concert.
The 5TMM Multiple Myeloma Model
To date, the 5TMM model is the only available spontaneous immune competent murine model for multiple myeloma that reflects key features of human MM, i.e. bone marrow tropism, secretion of monoclonal paraprotein, development of bone disease (osteolytic lesions) and development of tumor angiogenesis. Since the 5TMM model is an immune competent model, effects on the immune system, and particularly cell-cell interctions in the bone marrow niche, can be evaluated. The 5TMM model has been already proven to be useful in the analysis of the immune competent bone marrow niche.
modified from doi: 10.1242/dmm.008961 vol. 5 no. 6 763-771; j.exphem.2004.07.019
Translational Research & Clinical Significance
In MM, treatment regimens with immunomodulatory drugs and proteasome inhibitors have proven efficacy both as induction treatment prior to stem cell transplantation and first-line treatment for patients not eligible for transplantation, offering rapid and durable responses with consistently high rates of complete responses. However, the fact that most of the patients that achieve the currently defined status of a “complete remission” relapse later on, strongly suggests that clinically relevant MRD is not detectable by the parameters used today.
Thus, the major focus in the current development of treatment options for MM concentrates on achieving a deeper level of complete remission and a truly negative MRD-status. Therefore it is crucial to define the clinical significance of MRD and its impact on patient outcome.
Dr. rer. nat. Savita Bisht-Feldmann & Dr. med. Jens Nolting; Contact: firstname.lastname@example.org
Lab-members: Miriam-Ruth Reichelt (BTA), cand. med. Niklas Remke, cand. med. Jakob Reinke