Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer

Abstract

Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient’s antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the programmed death-1 (PD-1) pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunoregulatory tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. In this review, we focus on the role of PD-1-signaling in DC-mediated antitumor immunity. In the quest of exploiting the full potential of DC therapy, different strategies to leverage DC immunopotency by impeding PD-1-mediated immune regulation are discussed, including the most advanced research on targeted therapeutic antibodies, lessons learned from chemotherapy-induced immune activation, and more recent developments with soluble molecules and gene-silencing techniques. An overview of DC/PD-1 immunotherapy combinations that are currently under preclinical and clinical investigation substantiates the clinical potential of such combination strategies.

Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: results of a phase I trial

“…Immune checkpoint blockade is another strategy for combinational approaches. Early clinical trials are already combining vaccines with programmed cell death protein 1 (PD‐1) blockers for treatment of various malignancies including AML . The combination of both epigenetic modification by azacytidine and PD‐1 blockade by nivolumab was recently shown to be a safe and effective therapy for relapsed AML .…”

“…Early clinical trials are already combining vaccines with programmed cell death protein 1 (PD-1) blockers for treatment of various malignancies including AML. 27 The combination of both epigenetic modification by azacytidine and PD-1 blockade by nivolumab was recently shown to be a safe and effective therapy for relapsed AML. 28 However, other checkpoint molecules might be even more relevant as suggested by our preclinical data showing that blockade of lymphocyte activation gene 3 (LAG-3) strongly enhances DCinduced immune responses against viral and leukaemia-associated antigens.…”

TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab: link between T-cell activation and clinical responses in advanced melanoma

“…16 17 Therefore, more studies are now focusing on the combination of DC vaccines with PD-1 blocking antibodies, as reviewed in. 18 To our knowledge, none of these studies have published results yet. Interestingly, a recent publication showing that expanded T-cell clones detected on anti-PD-1 treatment are derived from clones that were absent in the tumor before the treatment, further supporting the combination of PD-1 blockade and active vaccination.…”

Gene-based Interventions for Cancer Immunotherapy

“…The efficiency of immunotherapies may be increased by applying combinations of different strategies. The combination of antibody therapy, cytokine therapy and checkpoint blockade with other immunotherapeutic strategies has been shown to increase antitumor activity [60][61][62]. Antibody therapy often targets tumor antigens and/or tumor-promoting proteins.…”