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Background <p>Intravesical Bacillus Calmette-Guérin (BCG) therapy has been the standard treatment for preventing recurrence of non-muscle-invasive bladder cancer (NMIBC) for over four decades. Although maintenance BCG therapy improves recurrence-free survival in intermediate- and high-risk NMIBC patients, its long treatment duration, toxicity, and limited efficacy - particularly in carcinoma in situ -necessitate the development of improved therapeutic alternatives. rBCG-h12 is a recombinant BCG strain engineered to enhance immunogenicity. This study evaluated its ability to augment macrophage activation and antitumor responses.</p> Methods <p>The safety of intravesical rBCG-h12 was evaluated in NOD/SCID and C57BL/6 mice through four weekly instillations. Body weight, survival, urine hematuria, and organ histopathology were monitored. Antitumor efficacy was tested using an orthotopic NMIBC transplant model. Immune microenvironment changes were analyzed by detecting macrophage and T cell markers. The systemic antitumor potential of rBCG-h12 was further evaluated via intramuscular injection in pancreatic cancer transplant and K-Ras<sup>G12D</sup> mouse models.</p> Results <p>Intravesical rBCG-h12 was well tolerated, with no observed mortality, weight loss, hematuria, or organ pathology. Compared with conventional BCG, rBCG-h12 more effectively suppressed bladder tumor growth, prolonged survival, and mitigated cachexia. Mechanistically, rBCG-h12 decreased CD206<sup>+</sup> M2-macrophages while increasing CD4<sup>+</sup>TNF-α<sup>+</sup> effector T cells and CD8<sup>+</sup>TNF-α<sup>+</sup> cytotoxic T cells. In pancreatic cancer models, a single intramuscular injection of rBCG-h12 markedly reduced desmoplasia, suppressed tumor growth, and extended survival without inducing pathological lesion or granuloma formation in liver, lungs, and spleen.</p> Conclusions <p>rBCG-h12 exhibited superior antitumor efficacy and safety compared with BCG. By suppressing M2-macrophages and promoting Th1 immune activation, rBCG-h12 shows promise as a next-generation BCG-based immunotherapy for both bladder and pancreatic cancers.</p>

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Preclinical evaluation of rBCG-h12: an engineered Bacillus Calmette-Guérin with an enhanced activity against bladder and pancreatic cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月1日

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  • Chang-Ching Yeh,
  • Chi-Shuan Fan,
  • Li-Li Chen,
  • Kee Voon Chua,
  • Chih-Hao Hsu,
  • Chia-Chi Chen,
  • Zhao-Lin Tan,
  • Pei-Chu Tsai,
  • Yung-Deng Song,
  • Yong-Seng Low,
  • Shiu-Ju Yang,
  • Yih-Yuan Chen,
  • Yi-Xiu Lin,
  • Chia-Ming Wu,
  • Horng-Yunn Dou,
  • Tze-Sing Huang

摘要

Background

Intravesical Bacillus Calmette-Guérin (BCG) therapy has been the standard treatment for preventing recurrence of non-muscle-invasive bladder cancer (NMIBC) for over four decades. Although maintenance BCG therapy improves recurrence-free survival in intermediate- and high-risk NMIBC patients, its long treatment duration, toxicity, and limited efficacy - particularly in carcinoma in situ -necessitate the development of improved therapeutic alternatives. rBCG-h12 is a recombinant BCG strain engineered to enhance immunogenicity. This study evaluated its ability to augment macrophage activation and antitumor responses.

Methods

The safety of intravesical rBCG-h12 was evaluated in NOD/SCID and C57BL/6 mice through four weekly instillations. Body weight, survival, urine hematuria, and organ histopathology were monitored. Antitumor efficacy was tested using an orthotopic NMIBC transplant model. Immune microenvironment changes were analyzed by detecting macrophage and T cell markers. The systemic antitumor potential of rBCG-h12 was further evaluated via intramuscular injection in pancreatic cancer transplant and K-RasG12D mouse models.

Results

Intravesical rBCG-h12 was well tolerated, with no observed mortality, weight loss, hematuria, or organ pathology. Compared with conventional BCG, rBCG-h12 more effectively suppressed bladder tumor growth, prolonged survival, and mitigated cachexia. Mechanistically, rBCG-h12 decreased CD206+ M2-macrophages while increasing CD4+TNF-α+ effector T cells and CD8+TNF-α+ cytotoxic T cells. In pancreatic cancer models, a single intramuscular injection of rBCG-h12 markedly reduced desmoplasia, suppressed tumor growth, and extended survival without inducing pathological lesion or granuloma formation in liver, lungs, and spleen.

Conclusions

rBCG-h12 exhibited superior antitumor efficacy and safety compared with BCG. By suppressing M2-macrophages and promoting Th1 immune activation, rBCG-h12 shows promise as a next-generation BCG-based immunotherapy for both bladder and pancreatic cancers.