Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression.

Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4+FoxP3+ regulatory T cells (Tregs) are highly abundant amongst CD4+ T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.

The use of bispecific antibodies to optimize the outcome of patients with acute leukemia, lymphoma and multiple myeloma after SCT.

One of the remaining and unresolved problems in allogeneic stem cell transplantation, especially following a T cell-depleted transplant as often performed in the setting of haploidentical transplantation, is the relapse of the underlying hematological malignancy. It has been demonstrated that in the last years we have made major progress in controlling infections, acute and chronic GvHD and making stem cell transplantation available to elderly patients. However, little improvement has been made to achieve better tumor control and to lower the relapse rate. Thus, novel immunotherapeutic strategies are increasingly used prior to or even following allogeneic stem cell transplantation to better control the underlying malignancy and thus, to reduce the relapse rate. These novel immunotherapeutic strategies comprise monoclonal antibodies, immunotoxins and even more effective T cell redirecting strategies like bispecific antibodies and T cells transduced with either chimeric antigen receptors (CAR) or (affinity-tuned) T cell receptors (TCR).