Molecular Determinants Underlying the Anti-Cancer Efficacy of CD38 Monoclonal Antibodies in Hematological Malignancies

Abstract

CD38 was first discovered as a T-cell antigen and has since been found ubiquitously expressed in various hematopoietic cells, including plasma cells, NK cells, B cells, and granulocytes. More importantly, CD38 expression levels on malignant hematopoietic cells are significantly higher than counterpart healthy cells, thus presenting itself as a promising therapeutic target. In fact, for many aggressive hematological cancers, including CLL, DLBCL, T-ALL, and NKTL, CD38 expression is significantly associated with poorer prognosis and a hyperproliferative or metastatic phenotype. Studies have shown that, beyond being a biomarker, CD38 functionally mediates dysregulated survival, adhesion, and migration signaling pathways, as well as promotes an immunosuppressive microenvironment conducive for tumors to thrive. Thus, targeting CD38 is a rational approach to overcoming these malignancies. However, clinical trials have surprisingly shown that daratumumab monotherapy has not been very effective in these other blood malignancies. Furthermore, extensive use of daratumumab in MM is giving rise to a subset of patients now refractory to daratumumab treatment. Thus, it is important to consider factors modulating the determinants of response to CD38 targeting across different blood malignancies, encompassing both the transcriptional and post-transcriptional levels so that we can diversify the strategy to enhance daratumumab therapeutic efficacy, which can ultimately improve patient outcomes.

Keywords: CD38; blood malignancies; daratumumab; drug combination; extracellular vesicles; immunotherapy; miRNA.

Figure 1

Functional roles of CD38. CD38 can mediate adhesion through binding with (1) hyaluronic acid in the extracellular matrix or through (2) binding with its cognate ligand CD31 to mediate adhesion and transendothelial migration. (3) Importantly, the ecto-enzymatic domain of CD38 catabolizes NAD+ into cADPR, which can enter the cell to mobilize calcium stores and modulate numerous cell signaling pathways. cADPR can also be hydrolyzed to ADPR, and then subsequently adenosine upon colocalization with CD73/203a. Adenosine is bound to purinergic receptors to suppress NK and T-cell activation.

Figure 2

A broad spectrum of mechanisms of action of daratumumab. Daratumumab triggers Fc-dependent immune effector mechanisms that comprise of CDC, ADCC, and ADCP. The Fc tail of daratumumab with the Fc gamma receptors (FcγRs) present on immune effector cells leads to activation of these immune cells and subsequent lytic killing of MM cells. Lysis and depletion of CD38+ immune suppressor cells, such as Tregs, also occur via the same process, leading to immunomodulation of the tumor niche and clonal expansion of cytotoxic T cell. CD38–daratumumab complexes that are formed are transferred from MM cells to monocytes and granulocyte in a process known as trogocytosis, thereby modulating CD38 expression on immune cells.

Figure 3

Molecular strategies to enhance CD38 expression and overall antitumor efficacy of Daratumumab. A. Transcriptional upregulation of the CD38 mRNA and subsequent protein expression can be stimulated by ATRA, HDAC inhibitors (panobinostat and ricolinostat), STAT3 inhibitor (ruxolitinib) and immunomodulatory drugs (pomalidomide and lenalidomide). B. CD38 mRNA can be degraded by miR-26a and miR-140-3p through direct binding to the 3’UTR or indirectly through the cytokine mediated mechanisms. These miRs can be targeted through antisense oligonucleotides to prevent CD38 mRNA degradation. C. Optimization of CD38 availability on the cell surface membrane by modulating processes involved in extracellular vesicle formation or trogocytosis.