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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
Author(s) -
Lin Xiaoyan,
Zhou Chunxia,
Wang Shengdian,
Wang Dongmei,
Ma Wenbo,
Liang Xiao,
Lin Chen,
Wang Zheng,
Li Jie,
Guo Sujuan,
Zhang Youhui,
Zhang Shuren
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22048
Subject(s) - telomerase reverse transcriptase , cytotoxic t cell , antigen , immunotherapy , cancer research , dna vaccination , cancer immunotherapy , biology , epitope , telomerase , monoclonal antibody , antibody , immunology , microbiology and biotechnology , virology , immune system , immunization , in vitro , gene , biochemistry
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. © 2006 Wiley‐Liss, Inc.