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Selective delipidation of Mycobacterium bovis BCG retains antitumor efficacy against non-muscle invasive bladder cancer

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Abstract

Purpose

Repeated instillations of bacillus Calmette et Guérin (BCG) are the gold standard immunotherapeutic treatment for reducing recurrence for patients with high-grade papillary non-muscle invasive bladder cancer (NMIBC) and for eradicating bladder carcinoma-in situ. Unfortunately, some patients are unable to tolerate BCG due to treatment-associated toxicity and bladder removal is sometimes performed for BCG-intolerance. Prior studies suggest that selectively delipidated BCG (dBCG) improves tolerability of intrapulmonary delivery reducing tissue damage and increasing efficacy in preventing Mycobacterium tuberculosis infection in mice. To address the lack of treatment options for NMIBC with BCG-intolerance, we examined if selective delipidation would compromise BCG’s antitumor efficacy and at the same time increase tolerability to the treatment.

Materials and methods

Murine syngeneic MB49 bladder cancer models and in vitro human innate effector cell cytotoxicity assays were used to evaluate efficacy and immune impact of selective delipidation in Tokyo and TICE BCG strains.

Results

Both dBCG-Tokyo and dBCG-TICE effectively treated subcutaneous MB49 tumors in mice and enhanced tumor-infiltrating CD8+ T and natural killer cells, similar to conventional BCG. However, when compared to conventional BCG, only dBCG-Tokyo retained a significant effect on intratumoral tumor-specific CD8+ and γδ T cells by increasing their frequencies in tumor tissue and their production of antitumoral function-related cytokines, i.e., IFN-γ and granzyme B. Further, dBCG-Tokyo but not dBCG-TICE enhanced the function and cytotoxicity of innate effector cells against human bladder cancer T24 in vitro.

Conclusions

These data support clinical investigation of dBCG-Tokyo as a treatment for patients with BCG-intolerant NMIBC.

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Acknowledgements

We would like to thank Alyssa M. Schami from Texas Biomedical Research Institute, Zhen-Ju Susan Shu from UT Health San Antonio, Chiou-Miin Wang and Nicholas D. Lucio from the BioAnalytics and Single-Cell Core (BASiC core) for technical support/assistance.

Funding

(1) San Antonio Medical Foundation 2019 fund (2) The Glenda and Gary Woods Distinguished Chair in GU Oncology (3) 8KL2 TR000118, K23, (4) the Mays Family Cancer Center at University of Texas Health San Antonio (P30 CA054174), (5) the Roger L. And Laura D. Zeller Charitable Foundation Chair in Urologic Cancer, (6) the Max & Minnie Tomerlin Voelcker Fund, (7) CDMRP CA170270/P1P2, (8) Bladder Cancer Advocacy Network (BCAN) 2016 Young Investigator Award, (9) Research Training Award (RP170345) from the Cancer Prevention & Research Institute of Texas.

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Author notes

  1. Niannian Ji and Meijun Long have contributed equally to this work.

Authors and Affiliations

  1. Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, TX, USA

    Niannian Ji, Neelam Mukherjee, Tyler J. Curiel & Robert S. Svatek

  2. Department of Urology, UT Health San Antonio, San Antonio, TX, USA

    Niannian Ji, Meijun Long, Neelam Mukherjee & Robert S. Svatek

  3. Breast Cancer Center, the 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China

    Meijun Long

  4. Population Health Program, TB Group, Texas Biomedical Research Institute, San Antonio, TX, USA

    Andreu Garcia-Vilanova, Russell Ault, Kizil A. Yusoof & Jordi B. Torrelles

  5. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Juan I. Moliva

  6. Division of Hematology/Medical Oncology at the UT Health San Antonio, San Antonio, TX, USA

    Tyler J. Curiel

  7. Chemistry and Chemical Engineering Division, Microencapsulation and Nanomaterials Department, Southwest Research Institute, San Antonio, TX, USA

    Hong Dixon

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  1. Niannian Ji
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Contributions

NJ contributed to concept, design, developing in vivo and in vitro models, supervising and performing studies, data acquisition and analysis, manuscript drafting and editing; ML contributed to designing and performing studies, data acquisition and analysis, manuscript editing; AGV contributed to preparation of delipidated BCG and control, protocol optimization, BCG cell-envelope lipids/delipidation analysis; RA contributed to concept and delipidated BCG preparation and protocol development; JIM contributed to concept and delipidated BCG protocol development; KAY contributed to delipidated BCG preparation; NM participated in developing mouse model and draft editing; TJC contributed to resources and expertise for acquiring flow cytometry data; HD contributed to grant acquisition and editing; JBT contributed to key concept, design, delipidated BCG protocol development, manuscript editing, grant acquisition; RSS contributed to key concept, design, grant acquisition, drafting manuscript and editing.

Corresponding authors

Correspondence to Jordi B. Torrelles or Robert S. Svatek.

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Conflict of interest

The studies related to this manuscript were conducted abided by research ethics and approved IACUC (#20120040AR) for animal or clinical sample use (IRB protocol HSC2012-159H). All authors have consent for publishing the data from these studies. Corresponding author R.S.S. discloses other roles as Consultant for FerGene and Clinical Research Support for JBL (SWOG), FKD and Decipher Biosciences. All other authors disclose no conflict of interest.

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Ji, N., Long, M., Garcia-Vilanova, A. et al. Selective delipidation of Mycobacterium bovis BCG retains antitumor efficacy against non-muscle invasive bladder cancer. Cancer Immunol Immunother 72, 125–136 (2023). https://doi.org/10.1007/s00262-022-03236-y

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  • DOI: https://doi.org/10.1007/s00262-022-03236-y

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