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Efficacy of intracellular immune checkpoint-silenced DC vaccine
Danhong Wang, … , Si-Yi Chen, Hu Chen
Danhong Wang, … , Si-Yi Chen, Hu Chen
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e98368. https://doi.org/10.1172/jci.insight.98368.
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Clinical Medicine Hematology Immunology

Efficacy of intracellular immune checkpoint-silenced DC vaccine

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Abstract

BACKGROUND. DC-based tumor vaccines have had limited clinical success thus far. SOCS1, a key inhibitor of inflammatory cytokine signaling, is an immune checkpoint regulator that limits DC immunopotency. METHODS. We generated a genetically modified DC (gmDC) vaccine to perform immunotherapy. The adenovirus (Ad-siSSF) delivers two tumor-associated antigens (TAAs), survivin and MUC1; secretory bacterial flagellin for DC maturation; and an RNA interference moiety to suppress SOCS1. A 2-stage phase I trial was performed for patients with relapsed acute leukemia after allogenic hematopoietic stem cell transplantation: in stage 1, we compared the safety and efficacy between gmDC treatment (23 patients) and standard donor lymphocyte infusion (25 patients); in stage 2, we tested the efficacy of the gmDC vaccine for 12 acute myeloid leukemia (AML) patients with early molecular relapse. RESULTS. gmDCs elicited potent TAA-specific CTL responses in vitro, and the immunostimulatory activity of gmDC vaccination was demonstrated in rhesus monkeys. A stage 1 study established that this combinatory gmDC vaccine is safe in acute leukemia patients and yielded improved survival rate. In stage 2, we observed a complete remission rate of 83% in 12 relapsed AML patients. Overall, no grade 3 or grade 4 graft-versus-host disease incidence was detected in any of the 35 patients enrolled. CONCLUSIONS. This study, with combinatory modifications in DCs, demonstrates the safety and efficacy of SOCS1-silenced DCs in treating relapsed acute leukemia. TRIAL REGISTRATION. ClinicalTrials.gov NCT01956630. FUNDING. National Institute of Health (R01CA90427); the Key New Drug Development and Manufacturing Program of the “Twelfth Five-Year Plan” of China (2011ZX09102-001-29); and Clinical Application Research of Beijing (Z131107002213148).

Authors

Danhong Wang, Xue F. Huang, Bangxing Hong, Xiao-Tong Song, Liangding Hu, Min Jiang, Bin Zhang, Hongmei Ning, Yuhang Li, Chen Xu, Xiao Lou, Botao Li, Zhiyong Yu, Jiangwei Hu, Jianlin Chen, Fan Yang, Haiyan Gao, Guoliang Ding, Lianming Liao, Lisa Rollins, Lindsey Jones, Si-Yi Chen, Hu Chen

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Figure 2

Enhanced priming of TAA-specific T cells by Ad-siSSF-DCs and enhanced TAA-specific CTL cytolytic activity against human tumor cells.

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Enhanced priming of TAA-specific T cells by Ad-siSSF-DCs and enhanced TA...
Human autologous T cells were cocultured with Ad-transduced DCs or PBS-treated hDCs (mock) (20:1) for 2 weeks. (A) Intracellular IFNG staining of cocultured CD4+ and CD8+ T cells. FACS analysis shows an increase of IFNG expression after coculture with Ad-siSSF-DCs compared with controls. (B) Increased IFNG-producing T cells after coculture with Ad-siSSF-DCs compared with coculture with controls is shown by ELISpot. Representative data from 1 of 5 HLA-A2+ donors are shown. (C) Cytolytic activities of HLA-A2+ T cells against various human tumor cell lines after 2 weeks of in vitro sensitization with different adenovirus-transfected autologous DCs were determined by standard 51Cr release assays. T cells sensitized by Ad-siSSF-DCs exhibited increased killing compared with those sensitized by controls. Cytolytic percentages are presented from 1 of 3 repeated experiments. Error bars represent mean ± SEM. *P < 0.05, Ad-siSSF vs. Ad-SM; **P < 0.01, Ad-siSSF vs. Ad-GFP or mock, as determined by Student’s 2-tailed t test.

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