Targeting the Bone Marrow Microenvironment
Unprecedented advances in multiple myeloma (MM) therapy during the last 15 years are predominantly based on our increasing understanding of the pathophysiologic role of the bone marrow (BM) microenvironment. Indeed, new treatment paradigms, which incorpor
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Abstract
Unprecedented advances in multiple myeloma (MM) therapy during the last 15 years are predominantly based on our increasing understanding of the pathophysiologic role of the bone marrow (BM) microenvironment. Indeed, new treatment paradigms, which incorporate thalidomide, immunomodulatory drugs (IMiDs), and proteasome inhibitors, target the tumor cell as well as its BM microenvironment. Ongoing translational research aims to understand in more detail how disordered BM-niche functions contribute to MM pathogenesis and to identify additional derived targeting agents. One of the most exciting advances in the field of MM treatment is the emergence of immune therapies including elotuzumab, daratumumab, the immune checkpoint inhibitors, Bispecific T-cell engagers (BiTes), and Chimeric antigen receptor (CAR)-T cells. This chapter will review our knowledge on the pathophysiology of the BM microenvironment and discuss derived novel agents that hold promise to further improve outcome in MM. Keywords
Bone marrow microenvironment Bone marrow Immune checkpoint inhibition CAR-T cells BiTEs
M. Moschetta Y. Kawano Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA K. Podar (&) Department of Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany e-mail: [email protected] © Springer International Publishing Switzerland 2016 A.M. Roccaro and I.M. Ghobrial (eds.), Plasma Cell Dyscrasias, Cancer Treatment and Research 169, DOI 10.1007/978-3-319-40320-5_6
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Introduction
The bone marrow (BM) environment consists of a cellular compartment with hematopoietic and nonhematopoietic cells and an extracellular compartment within a liquid milieu organized in a complex architecture of sub-microenvironments (“niches”) within the protective coat of the vascularized and innervated bone. The cellular BM compartment is composed of hematopoietic cells including hematopoietic and mesenchymal stem cells (HSCs, MSCs); hematopoietic and mesenchymal progenitor and precursor cells; mesenchymal stroma cells; BM-derived circulating endothelial precursors (EPCs); immune cells (B lymphocytes, T lymphocytes, natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), macrophages, monocytes, NKT cells, myeloid and plasmacytoid dendritic cells (mDCs, pDCs), regulatory T cells (Tregs), myeloid derived suppressor cells (MDSCs)); erythrocytes; megakaryocytes and platelets; and nonhematopoietic cells including adipocytes; endothelial progenitor cells (EPCs); endothelial cells (ECs); BM mesenchymal stroma cells (BM-MSCs); adipocytes; as well as cells involved in bone homeostasis including chondroclasts, osteoclasts (OCs), and osteoblasts (OBs). The extracellular compartment is composed of the extracellular matrix (ECM), an interlocking mesh of fibrous proteins and glycosaminoglycans. The liquid milieu contains a multitude of growth factors and cytokines; as well as matrix metalloproteinases. Moreover, the
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