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CD47 is a surface glycoprotein expressed by host cells to impede phagocytosis upon binding to macrophage SIRPα, thereby represents an immune checkpoint known as the “don't-eat-me” signal. However, accumulating evidence shows that solid and hematologic tumor cells overexpress CD47 to escape immune surveillance. Thus, targeting the CD47-SIRPa axis by limiting the activity of this checkpoint has emerged as a key area of research. In this review, we will provide an update on the landscape of CD47-targeting antibodies for hematological malignancies, including monoclonal and bi-specific antibodies, with a special emphasis on agents in clinical trials and novel approaches to overcome toxicity.

Increased levels of the nuclear export protein, exportin 1 (XPO1), were demonstrated in multiple myeloma (MM) patients. Targeting XPO1 with selinexor (the selective inhibitor of nuclear export; SINE compound KPT-330) demonstrates broad antitumor activity also in patient cells resistant to bortezomib; hence, it is a promising target in MM patients. Hypoxia is known to mediate tumor progression and drug resistance (including bortezomib resistance) in MM cells. In this study, we tested the effects of selinexor alone or in combination with bortezomib in normoxia and hypoxia on MM cell survival and apoptosis in vitro and in vivo. In vitro, selinexor alone decreased survival and increased apoptosis, resensitizing MM cells to bortezomib. In vivo, we examined the effects of selinexor alone on tumor initiation and tumor progression, as well as selinexor in combination with bortezomib, on tumor growth in a bortezomib-resistant MM xenograft mouse model. Selinexor, used as a single agent, delayed tumor initiation and tumor progression, prolonging mice survival. In bortezomib-resistant xenografts, selinexor overcame drug resistance, significantly decreasing tumor burden and extending mice survival when combined with bortezomib.