An innovative plasmacytoid dendritic cell line-based cancer vaccine primes and expands antitumor T-cells in melanoma patients in a first-in-human trial

Abstract

The efficacy of immune checkpoint inhibitors has been shown to depend on preexisting antitumor immunity; thus, their combination with cancer vaccines is an attractive therapeutic approach. Plasmacytoid dendritic cells (PDC) are strong inducers of antitumor responses and represent promising vaccine candidates. We developed a cancer vaccine approach based on an allogeneic PDC line that functioned as a very potent antigen-presenting cell in pre-clinical studies. In this phase Ib clinical trial, nine patients with metastatic stage IV melanoma received up to 60 million irradiated PDC line cells loaded with 4 melanoma antigens, injected subcutaneously at weekly intervals. The primary endpoints were safety and tolerability. The vaccine was well tolerated and no serious vaccine-induced side effects were recorded. Strikingly, there was no allogeneic response toward the vaccine, but a significant increase in the frequency of circulating anti-tumor specific T lymphocytes was observed in two patients, accompanied by a switch from a naïve to memory phenotype, thus demonstrating priming of antigen-specific T-cells. Signs of clinical activity were observed, including four stable diseases according to IrRC and vitiligoïd lesions. Four patients were still alive at week 48. We also demonstrate the in vitro enhancement of specific T cell expansion induced by the synergistic combination of peptide-loaded PDC line with anti-PD-1, as compared to peptideloaded PDC line alone. Taken together, these clinical observations demonstrate the ability of the PDC line based-vaccine to prime and expand antitumor CD8+ responses in cancer patients. Further trials should test the combination of this vaccine with immune checkpoint inhibitors.

BDCA1+ cDC2s, BDCA2+ pDCs and BDCA3+ cDC1s reveal distinct pathophysiologic features and impact on clinical outcomes in melanoma patients

“…Once activated via TLR7/9L, pDCs potentially achieve tumor control through efficient priming of antitumor responses 47,48 . Tumor antigen‐loaded pDCs properly activated can be vectors for immunotherapy and elicit favorable antitumor immune responses in patients upon vaccination 49,50 . Besides, the role of cDC1s in antitumor immunity, mostly described in mouse models, is poorly known in humans 51‐53 .…”

“…47,48 Tumor antigen-loaded pDCs properly activated can be vectors for immunotherapy and elicit favorable antitumor immune responses in patients upon vaccination. 49,50 Besides, the role of cDC1s in antitumor immunity, mostly described in mouse models, is poorly known in humans. [51][52][53] cDC1s are present in peripheral tissues where they capture tumor antigens and, after migration to tumordraining lymph nodes, activate antitumor CD4 + and CD8 + T cells.…”

Engineering a Human Plasmacytoid Dendritic Cell-Based Vaccine to Prime and Expand Multispecific Viral and Tumor Antigen-Specific T-Cells

“…We have developed several human plasmacytoid dendritic cell (PDC) lines from leukemic cells of a patient having a PDC leukaemia for research and development (R&D) applications [ 8 , 9 ] or for clinical applications [ 10 ]. One of them, the clinical-grade cell line named ‘PDC*line’ is grown in cell suspension in a synthetic medium without the need for any feeder cell, growth or maturation factor.…”

“…We also demonstrated that PDC*line cells were more potent than moDC to activate and expand potent antitumor T-cells [ 13 ]. With this PDC*line, we have developed a new cell-based vaccine approach named GeniusVac/PDC*vac that was first used to boost antitumor immunity in HLA-A*02:01 melanoma patients with a cell therapy product named GeniusVac-Mel4 [ 10 ]. The cell product was composed of the irradiated PDC*line cells loaded with four tumour HLA-A*02:01-restricted peptides derived from antigens expressed in melanoma.…”

“…This first-in-human trial demonstrated that the peptide-loaded PDC*line product was safe and not rejected. Importantly, we demonstrated that this PDC-based product was biologically active and, thus, able to induce the priming and expansion of circulating antitumor CD8 + T-cells in patients [ 10 ].…”