Abstract
In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion molecule interacting with CD31 and as an ectoenzyme. As an ectoenzyme, CD38 functions as a metabolic sensor catalyzing the extracellular conversion of NAD+ to the immunosuppressive factor adenosine (ADO). Other ectoenzymes, CD73 and CD203a, together with CD38, are also involved in the alternative axis of extracellular production of ADO, bypassing the canonical pathway mediated by CD39. CD38 is ubiquitously expressed in the bone marrow microenvironment; however, only MM cells display a very high surface density, which lead to the development of several anti-CD38 monoclonal antibodies (mAbs). The efficacy of anti-CD38 mAbs depends from the presence of CD38 on the surface of MM and immune-microenvironment cells. Interestingly, it has been reported that several drugs like lenalidomide, panobinostat, the all-trans retinoic acid and the DNA methyltransferase inhibitors may increase the expression of CD38. Hence, the possibility to modulate CD38 by increasing its expression on MM cells is the pre-requisite to potentiate the clinical efficacy of the anti-CD38 mAbs and to design clinical trials with the combination of anti-CD38 mAbs and these drugs.
Highlights
Multiple myeloma (MM) cells are characterized by tight relationship with the bone marrow (BM) microenvironment which supports their growth, survival, and induces drug resistance
Cells 2019, 8, 1632 modulate CD38 through an increase of its expression by MM cells is the pre-requisite to potentiate the efficacy of anti-CD38 monoclonal antibodies (mAbs)
Published data suggests that the use of IMiDs, all-trans retinoic acid (ATRA), and panobinostat may increase the clinical efficacy of anti-CD38 as DARA, isatuximab and MOR202
Summary
Multiple myeloma (MM) cells are characterized by tight relationship with the bone marrow (BM) microenvironment which supports their growth, survival, and induces drug resistance. Daratumumab (DARA) is the first anti- CD38 mAb approved for the treatment of relapsed and refractory MM based on the results of two phase I/II trials [3]. The combination of anti-CD38 mAbs with main anti-MM drugs as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) demonstrated a high clinical efficacy in randomized phase. The clinical efficacy of anti-CD38 mAbs seems to be related, at least in part, to the intensity of CD38 expression by MM cells and other cells of the immune-microenvironment. Cells 2019, 8, 1632 modulate CD38 through an increase of its expression by MM cells is the pre-requisite to potentiate the efficacy of anti-CD38 mAbs. Different pharmacological agents have demonstrated the capacity to increase the expression of CD38 by MM and BM microenvironment cells.
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