Efficacy of intracellular immune checkpoint-silenced DC vaccine
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
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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Clinical Research and Public Health Hematology Immunology

Efficacy of intracellular immune checkpoint-silenced DC vaccine

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 1

Enhanced maturation of Ad-siSSF–transduced hDCs.

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Enhanced maturation of Ad-siSSF–transduced hDCs. (A) Expression levels o...
(A) Expression levels of a panel of surface markers on human PBMC DCs at 48 hours after transduction with Ad-siSSF, control Ad-GFP virus (MOI = 25,000 vp), or PBS-treated (mock) (isotype controls: brown line). With the exception of OX40L and TLR5, all surface markers are upregulated after Ad-siSSF transduction compared with mock or Ad-GFP controls. (B) The levels of representative proinflammatory cytokines and chemokines in the culture media of human PBMC DCs 48 hours after transduction with different adenoviruses at a MOI of 25,000 vp, as analyzed by ELISA. The hDCs have significantly enhanced levels of these cytokines and chemokines after Ad-siSSF transduction compared with controls. (C) Migration rates of transduced human PBMC DCs in response to recombinant CCL21 (100 ng/ml) show the enhanced migratory activity of Ad-siSSF–transduced DCs compared with controls. Results are presented from 1 of 3 repeated assays (mean ± SEM). *P < 0.05, Ad-siSSF vs. Ad-SM DCs, as determined by Student’s 2-tailed t test.