Wang et al. designed an adenoviral vector (Ad-siSSF) encoding SOCS1 shRNA (an intracellular checkpoint inhibitor), two tumor-associated antigens, and bacterial flagellin (TLR5 agonist). Ad-siSSF-transduced human PBMC-derived DCs induced an antigen-specific cytotoxic T cell response in vitro and in rhesus monkeys. In a phase I clinical trial in relapsed AML and ALL, Ad-siSSF-DC treatment combined with cytokine-induced killer cells increased survival compared with donor lymphocyte infusion, and exhibited a favorable safety profile.
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).
Author Info: (1) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (2) Department of Molecular Microbiology and
Author Info: (1) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (2) Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA. (3) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA. (4) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA. (5) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (6) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (7) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (8) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (9) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (10) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (11) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (12) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (13) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (14) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (15) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (16) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (17) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (18) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China. (19) Department of Oncology, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China. (20) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA. (21) Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA. (22) Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA. (23) Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
