The clinical application of cancer immunotherapy based on naturally circulating dendritic cells

Abstract

Dendritic cells (DCs) can initiate and direct adaptive immune responses. This ability is exploitable in DC vaccination strategies, in which DCs are educated ex vivo to present tumor antigens and are administered into the patient with the aim to induce a tumor-specific immune response. DC vaccination remains a promising approach with the potential to further improve cancer immunotherapy with little or no evidence of treatment-limiting toxicity. However, evidence for objective clinical antitumor activity of DC vaccination is currently limited, hampering the clinical implementation. One possible explanation for this is that the most commonly used monocyte-derived DCs may not be the best source for DC-based immunotherapy. The novel approach to use naturally circulating DCs may be an attractive alternative. In contrast to monocyte-derived DCs, naturally circulating DCs are relatively scarce but do not require extensive culture periods. Thereby, their functional capabilities are preserved, the reproducibility of clinical applications is increased, and the cells are not dysfunctional before injection. In human blood, at least three DC subsets can be distinguished, plasmacytoid DCs, CD141 + and CD1c + myeloid/conventional DCs, each with distinct functional characteristics. In completed clinical trials, either CD1c + myeloid DCs or plasmacytoid DCs were administered and showed encouraging immunological and clinical outcomes. Currently, also the combination of CD1c + myeloid and plasmacytoid DCs as well as the intratumoral use of CD1c + myeloid DCs is under investigation in the clinic. Isolation and culture strategies for CD141 + myeloid DCs are being developed. Here, we summarize and discuss recent clinical developments and future prospects of natural DC-based immunotherapy.

Imaging of tumour response to immunotherapy

“…In this context, naturally circulating dendritic cells are isolated by leukapheresis (see below) and then loaded ex vivo with tumour antigens. Then, they are intravenousadministered into cancer patients to induce tumour-specific effector T cells aimed at recognising and eliminating cancer cells as well as inducing immunological memory to control tumour growth [6,8].…”

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

“…Peptide-based biologicals have significant potential as immunotherapeutic agents against several malignant cancers. Many studies [30][31][32][33] have approached the peptide-based cancer therapeutics development and their delivery by mirroring the corresponding functional sidegroups and domains of proteins having highly specific functions as immuno-regulators. Cancer immunotherapy using peptide-based therapeutics likely overcome the present problems of reaching only low levels inside the tumors and also the off-target effects in relation with the use of soluble checkpoint-blocking antibody.…”

Dendritic Cells and Their Roles in Anti-Tumour Immunity

“…In this method, DCs are isolated from patient peripheral blood mononuclear cells (PBMCs) obtained via leukapheresis, incubated with maturation stimuli and tumour Ags, and vaccinated back into the patient. Because this method requires a large number of DCs, and naturally circulating blood DCs are rare, the majority of clinical trials have previously used moDCs for this type of DC vaccine and have been extensively characterised [67,68].…”

“…Thus far, a wide variety of moDC vaccine strategies have been trialled [68]. moDCs have been differentiated and matured using monocyte conditioned medium with various supplements of cytokines (TNF-α, GM-CSF, IL-4, IFN-α), TLR agonists (LPS) and other factors such as prostaglandin E2 [67][68][69]. There is also variety in the type of Ags loaded into DCs such as peptides from tumour-associated Ags (TAA), TAA-encoding mRNA and whole tumour lysates [67].…”

“…moDCs have been differentiated and matured using monocyte conditioned medium with various supplements of cytokines (TNF-α, GM-CSF, IL-4, IFN-α), TLR agonists (LPS) and other factors such as prostaglandin E2 [67][68][69]. There is also variety in the type of Ags loaded into DCs such as peptides from tumour-associated Ags (TAA), TAA-encoding mRNA and whole tumour lysates [67]. More recently, the electroporation of synthetic mRNA encoding DC-maturation factors such as CD40 ligand, constitutively active TLR4 and CD70 together with fusion proteins DC-LAMP and melanoma-associated Ags into autologous moDCs (TriMixDC-MEL) have proven safe and immunogenic in phase 1 clinical trials in metastatic melanoma [70].…”