Research Article: Carfilzomib preserves dendritic cell phenotype and function compared with bortezomib

Abstract:
Despite major therapeutic advances, multiple myeloma (MM) remains largely incurable. Moreover, side effects and toxicities of treatments compromise patients’ quality of life. Dendritic cell (DC)-based cancer vaccines can induce long-term tumor-specific immune responses and are generally well tolerated. To improve the potency of this immunotherapeutic approach, researchers are now exploring combination strategies that integrate approved agents with DC-based vaccines. Proteasome inhibitors (PIs), including bortezomib and carfilzomib, are the standard of care for MM. PIs have been shown to induce so-called immunogenic cell death and could therefore be promising agents for combination approaches. However, careful selection of the optimal drug is mandatory, as off-target effects may also hamper the immune system, as previously shown for bortezomib. By flow cytometry, we systematically evaluated the effects of the PI carfilzomib on the phenotype and expression of immune checkpoint molecules in monocyte-derived human DCs (moDCs) compared to bortezomib. Functional analyses included endocytosis, migration, cytokine secretion, and T cell stimulatory capacity in mixed lymphocyte reactions (MLRs), with and without PD-1 blockade. We assessed DC frequencies in peripheral blood and bone marrow of MM patients at diagnosis, during carfilzomib-based therapy, and in remission and further generated DCs using monocytes of carfilzomib-treated patients. Carfilzomib exposure did not compromise moDC characteristics, including phenotype, endocytosis, migration, and cytokine secretion, in vitro, whereas bortezomib-exposed moDCs differed significantly in several parameters. Carfilzomib modestly increased PD-L1 expression on moDCs and significantly reduced both their allostimulatory capacity and the IFN-? production of cocultured T cells. PD-1 blockade with nivolumab fully reversed this effect and significantly enhanced it in MLR. We assessed reduced numbers of circulating DCs in MM patients at diagnosis, but numbers were comparable to those in healthy donors, patients receiving carfilzomib-based therapy and patients in remission. Furthermore, we could generate moDCs with a typical surface phenotype from monocytes of patients receiving carfilzomib-based therapy. Our findings show that carfilzomib does not cause the broad impairment seen with bortezomib, and that the discrete deficit it does produce is reversible with PD-1 blockade. We hypothesize that carfilzomib is a more suitable proteasome inhibitor partner for DC-based immunotherapeutic strategies.

Introduction:
Despite major therapeutic advances, multiple myeloma (MM) remains largely incurable. Moreover, side effects and toxicities of treatments compromise patients’ quality of life. Dendritic cell (DC)-based cancer vaccines can induce long-term tumor-specific immune responses and are generally well tolerated. To improve the potency of this immunotherapeutic approach, researchers are now exploring combination strategies that integrate approved agents with DC-based vaccines. Proteasome inhibitors (PIs), including…

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