Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Abstract

The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

Daratumumab and Nanobody-Based Heavy Chain Antibodies Inhibit the ADPR Cyclase but not the NAD+ Hydrolase Activity of CD38-Expressing Multiple Myeloma Cells

“…The tumor microenvironment promotes the growth of multiple myeloma cells in bone marrow niches and hampers anti-tumor immune responses [ 1 , 2 ]. The tumor microenvironment is characterized by hypoxia, acidic pH, high concentration of disulfide reducing agents, and enzymes that convert the endogenous danger signals ATP and NAD + into immunosuppressive adenosine [ 3 , 4 , 5 ].…”

Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities

“…BM-mediated immune dysfunction and tumor immune evasion represent the main challenges for immunotherapy in MM ( 5 ). However, although qualitative and/or quantitative alterations of cellular and non-cellular components of the BM niche in MM confer immunosuppression, they similarly represent ideal targets for novel therapeutics.…”

Multiple myeloma: the (r)evolution of current therapy and a glance into future

“… 107-109 Similarly, myeloid derived suppressor cells, regulatory T cells, Th17 cells, tumor-associated macrophages, mesenchymal stromal cells, and osteoclasts significantly contribute to tumor immune escape and immunocompromised clinical status. 110 Immune escape is also mediated, at least in part, by increased expression of immune checkpoints, i.e., PD-1/PD-L1, in T cells and MM cells, associated with disease progression from MGUS and SMM to MM. 111 Although preclinical data have suggested the therapeutic utility of PD-1/PD-L1 blockade, early clinical trials have been discouraging.…”