Our lab is located in the blood cancer and bone marrow transplant program of the hematology division of the University of Colorado Anschutz Medical campus. Our research focus is in therapeutic optimization for multiple myeloma, especially for patients with drug resistant and advanced disease. In particular, we are interested in helping develop and apply new immunotherapies to myeloma, especially antibody-based therapies. The following sections illustrate the core philosophies of our research program.
Myeloma cells under the microscope, crowding out the normal bone marrow cells. Photo credit to Jessica Davis, MD.
Multiple myeloma is a debilitating blood cancer that afflicts more than 30,000 Americans each year. There is much to be done to improve patients’ lives and finding a cure is achievable. Although the treatment has greatly improved in the past decade, no current therapy is capable of fully eliminating minimal residual disease in most patients. Myeloma is derived from plasma cells, which are responsible for antibody-based immunity. When they become cancerous, myeloma cells secrete monoclonal antibody that causes severe symptoms and also serves as a way to monitor the level of disease. Myeloma cells are susceptible to drugs that exploit their unique attributes, the protease inhibitors and IMiDs.
Exciting breakthroughs have been made in the development of new immunotherapies for multiple myeloma. Myeloma is readily accessible to antibody-based therapies in the bone marrow and thus an ideal disease for this drug class. Recently, myeloma targeted naked antibodies have shown groundbreaking clinical activity. Now potential for further improved clinical effects has emerged with antibody-drug conjugates and bispecific antibodies. Our focus is on the development of these antibody-based therapies and optimizing how they are applied, both in terms of finding patient subpopulations that will benefit most and in rational design of drug combination strategies.
Naked antibodies attract components of the immune system, such as macrophages and natural killer (NK) cells to kill myeloma cells. Bispecific antibodies bind both myeloma and T-cells, activating the powerful killing activity of these cells. Antibody-drug conjugates are a targeted delivery system for highly potent chemotherapy directly into the myeloma cells.
Flow cytometry of a bone marrow sample from a patient with myeloma. (Right panel) Bone marrow contains a complex mixture of immune cells and blood cell progenitors that come in all shapes in sizes. (Left panel) Differentiating myeloma cells from this mixture requires the use of multiple cell surface markers with known expression patterns on these cells, such as CD38.
The pipeline for new myeloma drugs is highly active, but completely dependent on cell line models, which don’t accurately reflect the disease in many ways. Thus, a priority for our lab is to bank tissue samples from patients with myeloma at UC Denver. Bone marrow aspirates are obtained clinically at diagnosis and relapse. Donation of an aliquot for research purposes allows us to examine a number of facets of disease biology and optimize its treatment. Among the most important technologies we apply is flow cytometry (aka FACS analysis). This technique allows the isolation of the malignant myeloma population from heterogeneous mixtures of cells for further genetic and phenotypic analyses.
Evolution of Drug Resistance
Another focus of our lab is the real-time characterization of inherent and acquired drug resistance in our patients using ex vivo drug sensitivity testing. This approach could be useful across the disease history of our patients as they are cycled through sequential lines of therapy. The mechanisms of drug resistance in multiple myeloma are diverse, a function of the variety of agents that are effective against the disease. Improved knowledge in this area could potentially personalize treatment selection and aid drug development for patients with long-standing disease that have inevitably developed resistance to all the clinically approved therapies.
Targeting Myeloma Cells that Comprise Minimal Residual Disease
The current problem in myeloma is that no therapy is capable of eliminating minimal residual disease (MRD), preventing cure, and inevitably leading to disease relapse in all patients. MRD contains cells that have disease regenerating capacity, behaving functionally as “myeloma stem cells” that eventually lead to relapse. It is our hope to develop a therapy approach capable of eliminating MRD, yielding curative potential for this disease. Towards this we are implementing patient sample derived, MRD-focused strategies, including ex vivo assays of self-renewal activity and xenograft models for the testing of novel anti-myeloma therapeutics.