Development and validation of delipidated Mycobacterium bovis Calmette et Guérin (dBCG) ...

Development and validation of delipidated Mycobacterium bovis Bacille CalmetteetGuérin(dBCG) as an improvement of the original TBvaccine and as a treatment candidate for bladder cancer

Mycobacterium bovis Bacille Calmette et Guérin (BCG) was one of the first vaccines ever developed. Originally generated to combat Tuberculosis, it has been a polemic vaccine over its 100 years of existence, with different countries adopting diverging vaccination programs due to its variable efficacy to protect against pulmonary Tuberculosis. Despite Tuberculosis being one of the world’s deadliest diseases, with almost one third of the world’s population latently infected with Mycobacterium tuberculosis, and 1.2 million deaths each year, there is limited number of new vaccines against Tuberculosis tested currently in human clinical trials. Current BCG administration is intramuscular; thus, to improve BCG efficacy the Tuberculosis scientific community is looking at alternative routes of administration. Our laboratory, through a series of selective delipidations, is able to remove selectively some of the lipids from the BCG cell envelope, without inactivating the bacterium. This allowed us to directly deliver dBCG into the lungs, and mount a specific and more protective memory immune response in the tissue where M. tuberculosis infection normally occurs, the lung. Currently, we are testing dBCG in conjunction with other immunomodulators to further increase the efficacy of our dBCG vaccine. Additionally, benefits derived from our dBCG vaccination strategies may also apply to bladder cancer treatment, showing promise as a possible treatment strategy for this pathology.

Representative Papers

  • Ji, Niannian, Meijun Long, Andreu Garcia-Vilanova, Russell Ault, Juan I Moliva, Kizil A Yusoof, Neelam Mukherjee, et al. (2023) 2023. “Selective Delipidation of Mycobacterium Bovis BCG Retains Antitumor Efficacy Against Non-Muscle Invasive Bladder Cancer.”. Cancer Immunology, Immunotherapy : CII 72 (1): 125-36. https://doi.org/10.1007/s00262-022-03236-y.
    Publisher's Version

    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.

  • Moliva, Juan I, Austin P Hossfeld, Sabeen Sidiki, Cynthia H Canan, Varun Dwivedi, Gillian Beamer, Joanne Turner, and Jordi B Torrelles. (2019) 2019. “Selective Delipidation of Mycobacterium Bovis BCG Enables Direct Pulmonary Vaccination and Enhances Protection Against Mycobacterium Tuberculosis.”. Mucosal Immunology 12 (3): 805-15. https://doi.org/10.1038/s41385-019-0148-2.
    Publisher's Version

    Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is the leading killer due to an infectious organism. Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only vaccine approved against TB, however, its efficacy against pulmonary TB is poor. While BCG is currently inoculated intradermally, the natural route of M.tb infection is through the lung. Excessive lung pathology caused by pulmonary inoculation of BCG has prevented the use of this immunization route. Here, we show that selective chemical treatment of BCG with petroleum ether removes inflammatory lipids from the bacterial surface while keeping BCG viable. Pulmonary vaccination using this modified BCG attenuated inflammatory responses, prevented immunopathology of the lung, and significantly increased protection against M.tb infection in mice. We further directly linked IL-17A as the responsible contributor of improved immunity against M.tb infection. These results provide evidence that selective removal of cytotoxic lipids from the BCG surface attenuates inflammation and offers a safer and superior vaccine against TB causing less damage post-infectious challenge with M.tb.