Characterization of Interleukin-15-Transpresenting Dendritic Cells for Clinical Use

Abstract

Personalized dendritic cell- (DC-) based vaccination has proven to be safe and effective as second-line therapy against various cancer types. In terms of overall survival, there is still room for improvement of DC-based therapies, including the development of more immunostimulatory DC vaccines. In this context, we redesigned our currently clinically used DC vaccine generation protocol to enable transpresentation of interleukin- (IL-) 15 to IL-15Rβγ-expressing cells aiming at boosting the antitumor immune response. In this study, we demonstrate that upon electroporation with both IL-15 and IL-15Rα-encoding messenger RNA, mature DC become highly positive for surface IL-15, without influencing the expression of prototypic mature DC markers and with preservation of their cytokine-producing capacity and their migratory profile. Functionally, we show that IL-15-transpresenting DC are equal if not better inducers of T-cell proliferation and are superior in tumor antigen-specific T-cell activation compared with DC without IL-15 conditioning. In view of the clinical use of DC vaccines, we evidence with a time- and cost-effective manner that clinical grade DC can be safely engineered to transpresent IL-15, hereby gaining the ability to transfer the immune-stimulating IL-15 signal towards antitumor immune effector cells.

mRNA therapeutics in cancer immunotherapy

“…mRNA-encoded cytokines are another class of molecules used to enhance DC maturation and T-cell priming capacity. In the context of autologous DC vaccines loaded with whole tumor mRNA preparations or with synthetic TAA-encoding mRNA, co-transfection with cytokine-encoding mRNA, such as GM-CSF, IL-12 and IL-15, was explored [ 80 – 84 ]. Co-transfection of GM-CSF mRNA into tumor mRNA-loaded DCs significantly enhanced the anti-tumor efficacy of DC vaccines in CT26 tumor-bearing mice, which was associated with increased cytotoxicity of bulk splenocytes against CT26 tumor cells in vitro [ 80 ].…”

Ex vivo IL-15 replenishment augments bone marrow precursor cell-mediated adaptive immunity via PI3K-Akt pathway

“…Hence, in vivo direct IL‐15 administration affects many types of cell differentiation and has no therapeutic potential 10 . Personalized DC‐based vaccination, instead of direct IL‐15 administration in vivo, is a safe and effective therapy against various tumors 34 . In the present study, PI3K‐Akt activity was evidenced to facilitate ex vivo IL‐15 increased therapeutic potential of BMPC‐based vaccination, indicating that PI3K‐Akt might be potential molecules for IL‐15 augmented BMPC‐mediated adaptive immunity.…”

Messenger RNA vaccines for cancer immunotherapy: progress promotes promise

“…mRNA-based vaccines provide a platform for co-delivering a range of immunomodulatory agents, thus allowing a fine-tuning of T cell responses. For example, co-delivery of stimulatory cytokines, such as GM-CSF, IL-12, and IL-15, with mRNA encoding tumor antigen in dendritic cell vaccines promotes remodeling of the TME, enhances cytotoxic T cell responses, and controls tumor growth in preclinical models (128)(129)(130)(131). Further, in situ vaccination with a cocktail of naked mRNAs encoding IL-12, GM-CSF, IL-15, and IFN-α4 promotes tumor infiltration of polyfunctional Th1-like CD4 + cells, cytotoxic CD8 + T cells, and pro-immune monocytic cell types while decreasing Tregs, leading to survival benefits in murine models of cancer including metastatic melanoma (132).…”