Augmenting DC function for rational immunotherapies in multiple myeloma

Abstract

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the infiltration of the bone marrow by malignant plasma B cells. Despite the approval of novel agents, MM remains an incurable disease and side effects of treatment seriously impair quality of life. Novel therapeutic approaches are needed comprising long-lasting response and low toxicities. Dendritic cells (DC)-based cancer vaccines are a promising immunotherapeutic strategy able to elicit long-lasting anti-cancer immunity and are well tolerable. DC are the most potent antigen-presenting cells (APC) that coordinate innate and adaptive immune responses and hence play a central role in immunotherapeutic approaches. However, cancer vaccines alone have failed to achieve expectations with respect to clinical outcomes. Bortezomib and carfilzomib are proteasome inhibitors that are approved as powerful anti-tumor agents in MM treatment. Recently, they were further shown to be immunogenic cell death (ICD) inducing drugs capable of inducing a type of immunostimulatory apoptosis. However, studies demonstrate that bortezomib significantly impairs DC phenotype and functions. Carfilzomib, a second-generation proteasome inhibitor with less off-target effects, could be a promising combinatory agent. The efficacy of the vaccine may further be augmented by immune checkpoint inhibition (ICI). Our goal is to investigate the effect of carfilzomib on DC combined with ICI to provide more evidence for the exploration of a combinatory approach in MM treatment. Methods: Effects of carfilzomib and bortezomib on human monocyte-derived DC (moDC) differentiation, phenotype including immune checkpoints, and function were comparatively analyzed by FACS, ELISA, and MLR in vitro. Additionally, the quantity of peripheral blood DC in newly diagnosed carfilzomib-treated MM patients was measured and data was compared to healthy donors. Results: Carfilzomib had only minor effects on DC differentiation, phenotype, and function. The expression of immune checkpoint programmed death ligands 1 (PD-L1) was significantly upregulated under carfilzomib exposure. Carfilzomib-exposure led to reduced T cell proliferation in MLR which could not only be leveled out, but enhanced by the addition of an anti-PD-1 antibody. Analyses of patient samples showed reduced numbers of peripheral blood and bone marrow DC at diagnosis compared to healthy donors. However, numbers recovered under treatment with carfilzomib-containing reg-imens. Conclusions: Carfilzomib represents an appropriate standard of care drug for combinatorial approaches with a DC-based cancer vaccine. The efficacy of the vaccine can possibly be augmented by the combination with approved ICI. Such combinatory ap-proaches have the potential to induce long-term immune responses and disease control without increasing toxicity.