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Treatment of bladder carcinomas using recombinant BCG DNA vaccines and electroporative gene immunotherapy

Cancer Gene Therapy volume 11, pages 194–207 (2004)Cite this article

Abstract

Intravesical immunotherapy with live Mycobacterium bovis bacillus Calmette–Guérin (BCG) is the treatment of choice for superficial bladder cancers. Nevertheless, a significant proportion of patients do not respond to this therapy, and adverse effects are common. Here, we report the cloning of recombinant mycobacterial DNA vaccines and demonstrate the ability of multicomponent and multisubunit DNA vaccines to enhance Th1-polarized cytokine-mediated responses as well as effector cell responses. Splenocytes from immunized groups of mice were restimulated in vitro and examined for cytotoxicity against murine bladder tumur (MBT-2) cells. We used four combined recombinant BCG DNA vaccines (poly-rBCG) for electroporative gene immunotherapy (EPGIT) in vivo, and found that tumor growth was significantly inhibited and mouse survival was prolonged. Increased immune cell infiltration and induction of apoptosis were noted after treatment with poly-rBCG alone, with the murine interleukin-12 (mIL-12) vaccine alone, and—most significantly—with the poly-rBCG+mIL-12 vaccine combination. Electroporation of poly-rBCG+mIL-12 resulted in complete tumor eradication in seven of eight mice (P<.01) within 28 days. Thus, EPGIT using multicomponent multisubunit BCG is highly effective in the treatment of bladder cancer. This approach presents new possibilities for the treatment of bladder cancer using recombinant BCG DNA vaccines.

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Abbreviations

BCG:

bacillus Calmette–Guérin

CBA:

cytometric bead array

CTL:

cytotoxic T lymphocyte

EPGIT:

electroporative gene immunotherapy

FITC:

fluorescein isothiocyanate

H&E:

haematoxylin and eosin

Igk:

immunoglobulin kappa

MBT-2:

murine bladder tumor

poly-rBCG:

four combined recombinant BCG DNA vaccines

TUNEL:

terminal dUTP nick-end labeling

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Acknowledgements

This work was supported by a grant from the National Science Council (NSC91-2314-B-016-097) and the Shuyuan Education and Academic Promotion Foundation. We thank professor Luke S Chang, Chun-Hsiung Huang, Ming-Kun Lai, and Guang-Huan Sun for their insightful comments. We are grateful to Dr Shan-Chih Lee and Ms Wen-Yi Ma for their technical assistance, Dr Lu Bie for the discussion with statistical analyses, Dr Jah-Fu Shyue for the microscope operation, and the staff of the National Defense Medical Center of Animal Center for assistance with the care of animals under challenging conditions.

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Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defence Medical Centre, National Defence University, Taipei, ROC, Taiwan

    Chi-Feng Lee

  2. National Defence Medical Bureau, Ministry of National Defence, Taipei, ROC, Taiwan

    Sun-Yran Chang

  3. Division of Urology, Department of Surgery, Laboratory of Uro-oncology, Tri-Service General Hospital, Taipei, ROC, Taiwan

    Chi-Feng Lee, Dar-Shih Hsieh & Dah-Shyong Yu

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Correspondence to Dah-Shyong Yu.

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Lee, CF., Chang, SY., Hsieh, DS. et al. Treatment of bladder carcinomas using recombinant BCG DNA vaccines and electroporative gene immunotherapy. Cancer Gene Ther 11, 194–207 (2004). https://doi.org/10.1038/sj.cgt.7700658

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