title: Enhanced antitumor effect against human telomerase reverse transcriptase (hTERT) by vaccination with chemotactic-hTERT gene-modified tumor cell and the combination with anti-4-1BB monoclonal antibodies.
abstract: Human telomerase reverse transcriptase (hTERT) represents an attractive target for cancer immunotherapy because hTERT is reactivated in most human tumors. In an attempt to develop an effective vaccine against most human cancers, we constructed chemotactic-hTERT vaccine. Two hTERT fragments encoding multiple cytotoxic T lymphocyte and T helper cell epitopes were fused as a tumor antigen (named Te). The plasmid based DNA vaccine (pCCL21-Te-Fc) was constructed by linking human CCL21 and IgG Fc gene sequences to each end of Te. In poorly immunogenic B16F10 mouse melanoma model, DNA (pCCL21-Te-Fc) vaccination significantly inhibited tumor growth and all of the mice were dead by day 52. The immunization with pCCL21-Te-Fc-modified tumor cells (B16/CCL21-Te-Fc) resulted in a higher antitumor effect than DNA vaccination and 25% of tumor-bearing mice achieved long-term survival (> 120 days). The combined therapy of B16/CCL21-Te-Fc plus anti-4-1BB MAbs further enhanced the immune response, resulting in 75% of tumor-bearing mice achieved long-term survival (> 120 days) in subcutaneous model and few lung nodules in pulmonary metastasis model. Rechallenge experiment showed that a persistent memory response was successfully induced by the combined therapy. In vivo depletion of lymphocytes indicated that CD8+ T cells were essential in the antitumor activity induced by B16/CCL21-Te-Fc plus anti-4-1BB MAbs, whereas NK cells and CD4+ T cells played substantial roles. The CTL activity induced by pCCL21-Te-Fc-transfected PBMCs specifically lysed a variety of human leukocyte antigen-matched and hTERT-positive human tumor cells, suggesting pCCL21-Te-Fc could serve as a vaccine against most human cancers.
authors.affiliation: Department of Immunology, Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Lin
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zhou
authors.forename: Shengdian
authors.initials: S
authors.lastname: Wang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.forename: Wenbo
authors.initials: W
authors.lastname: Ma
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.forename: Chen
authors.initials: C
authors.lastname: Lin
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Sujuan
authors.initials: S
authors.lastname: Guo
authors.forename: Youhui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shuren
authors.initials: S
authors.lastname: Zhang
mesh_terms: D053330:4-1BB Ligand; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D002478:Cells, Cultured; D002633:Chemotaxis; D004247:DNA / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015234:HLA-A Antigens / Q000276:immunology; D015788:HLA-A1 Antigen; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D010957:Plasmids / Q000235:genetics; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D015234:HLA-A Antigens; C432723:HLA-A*01:03 antigen; D015788:HLA-A1 Antigen; C505974:TNFSF9 protein, human; C505975:Tnfsf9 protein, mouse; D048069:Tumor Necrosis Factors; D019444:Vaccines, DNA; D004247:DNA; D019098:Telomerase