Transfer of Cellular Content from the Allogeneic Cell-Based Cancer Vaccine DCP-001 to Host Dendritic Cells Hinges on Phosphatidylserine and Is Enhanced by CD47 Blockade.

Haoxiao Zuo,Erik H Manting,Ada M Kruisbeek,Alex Karlsson-Parra,Tanja D De Gruijl,Saheli Sarkar,Gijs Kooij,Marie-José C Van Lierop,Anneke Reurs,Satwinder Kaur Singh,Helga E De Vries,Tania Konry,Alwin Kamermans,Remco Bos,Jorn Kaspers

doi:10.3390/cells10113233

Haoxiao Zuo, Erik H Manting + Show 13 more

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https://doi.org/10.3390/cells10113233

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Abstract

DCP-001 is a cell-based cancer vaccine generated by differentiation and maturation of cells from the human DCOne myeloid leukemic cell line. This results in a vaccine comprising a broad array of endogenous tumor antigens combined with a mature dendritic cell (mDC) costimulatory profile, functioning as a local inflammatory adjuvant when injected into an allogeneic recipient. Intradermal DCP-001 vaccination has been shown to be safe and feasible as a post-remission therapy in acute myeloid leukemia. In the current study, the mode of action of DCP-001 was further characterized by static and dynamic analysis of the interaction between labelled DCP-001 and host antigen-presenting cells (APCs). Direct cell–cell interactions and uptake of DCP-001 cellular content by APCs were shown to depend on DCP-001 cell surface expression of calreticulin and phosphatidylserine, while blockade of CD47 enhanced the process. Injection of DCP-001 in an ex vivo human skin model led to its uptake by activated skin-emigrating DCs. These data suggest that, following intradermal DCP-001 vaccination, local and recruited host APCs capture tumor-associated antigens from the vaccine, become activated and migrate to the draining lymph nodes to subsequently (re)activate tumor-reactive T-cells. The improved uptake of DCP-001 by blocking CD47 rationalizes the possible combination of DCP-001 vaccination with CD47 blocking therapies.

Highlights

DCP-001 induced a stronger proliferative response in allogeneic Peripheral blood lymphocytes (PBLs) (Figure 1B) and, in allogeneic peripheral blood mononuclear cells (PBMCs), induced release of pro-inflammatory cytokines and chemokines, including type-1 T-cell cytokines, at levels far exceeding those induced by DCOne (Figure 1C)
DCP-001 itself released IL-1β, which was not observed for DCOne
DCP-001 is an allogeneic cell-based vaccine differentiated from the DCOne cell line

Summary

Introduction

Current approaches in cancer vaccine development include cellular vaccines consisting of either killed cancer cells or autologous antigen-presenting cells (APCs) loaded with cancer antigens. Major challenges facing the development of these vaccines are low immunogenicity and, except for whole tumor cell-based vaccines, 4.0/). Autologous cellular vaccines often suffer from lack or shortage of patient-derived tumor cells or high variability in patient-derived APCs and a complex manufacturing process with a complicated supply chain. To overcome these hurdles the use of allogeneic cells is currently extensively studied as an alternative approach with the additional advantage of inducing a stronger immune response [1,2,3]. The need for an intact immune compartment for an optimal immune response to allogeneic DC-based vaccines facilitates the use of these vaccines in comparison to other allogeneic immunotherapies, such as allogeneic CAR-T cell therapies, which usually need prior patient lymphodepletion or immunosuppression to overcome host immune rejection and to limit graft-versus-host disease

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