TY  - JOUR
A1  - Dahlhoff, Julia
A1  - Manz, Hannah
A1  - Steinfatt, Tim
A1  - Delgado-Tascon, Julia
A1  - Seebacher, Elena
A1  - Schneider, Theresa
A1  - Wilnit, Amy
A1  - Mokhtari, Zeinab
A1  - Tabares, Paula
A1  - Böckle, David
A1  - Rasche, Leo
A1  - Martin Kortüm, K.
A1  - Lutz, Manfred B.
A1  - Einsele, Hermann
A1  - Brandl, Andreas
A1  - Beilhack, Andreas
T1  - Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression
JF  - Leukemia
N2  - 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.
KW  - Multiple myeloma
KW  - transient regulatory T-cell targeting
KW  - immune control
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271787
SN  - 1476-5551
VL  - 36
IS  - 3
ER  - 
TY  - JOUR
A1  - Da Vià, Matteo Claudio
A1  - Solimando, Antonio Giovanni
A1  - Garitano-Trojaola, Andoni
A1  - Barrio, Santiago
A1  - Munawar, Umair
A1  - Strifler, Susanne
A1  - Haertle, Larissa
A1  - Rhodes, Nadine
A1  - Vogt, Cornelia
A1  - Lapa, Constantin
A1  - Beilhack, Andreas
A1  - Rasche, Leo
A1  - Einsele, Hermann
A1  - Kortüm, K. Martin
T1  - CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF‐MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement
JF  - The Oncologist
N2  - Combined MEK‐BRAF inhibition is a well‐established treatment strategy in BRAF‐mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF‐MEK inhibitor treatment are unavailable.

Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high‐risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient.
KW  - Multiple myeloma
KW  - Extramedullary disease
KW  - Capicua transcriptional repressor
KW  - Drug resistance
KW  - BRAF mutation
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219549
VL  - 25
IS  - 2
ER  -