Recently, pembrolizumab (antiPD-1), was granted approval for BCG-unresponsive NMIBC (KEYNOTE-057, NCT02625961), although results showed less than 18 % complete responses without recurrence at 1 year.2
Given the historical success of BCG in the treatment of NMIBC, it is not surprising that efforts have been made to genetically modify this vaccine to make it more effective for bladder cancer treatment. Recent examples include the recombinant BCG strain VPM1002BC, which was tested in a phase I/II clinical trial with promising results,3 or a BCG strain overexpressing cyclic-di-AMP which showed improved efficacy in experimental animal models.4 Moreover, BCG strains have been reported to differ in their efficacy against bladder cancer in humans and animal models,5 meaning that genetic differences between bacterial strains influence their antitumoral efficacy. Another strategy is finding other bacteria different from BCG that could improve it. Recent examples include Ty21a/Vivotif, a commercial vaccine against typhoid fever that showed efficacy as intravesical treatment in preclinical models.6
MTBVAC is a live mycobacterial vaccine obtained by rational attenuation of a clinical isolate of Mycobacterium tuberculosis, which is expected to start phase III clinical trials for the prevention of tuberculosis.7 Unlike BCG, which was attenuated from Mycobacterium bovis, a cattle pathogen, MTBVAC comes from the human pathogen. The genetic differences between BCG and MTBVAC are mostly defined, and we initially hypothesized that these differences might affect their behavior as intravesical therapy for bladder cancer.
In our work recently published in Journal for ImmunoTherapy of Cancer,8 we compared the efficacy of BCG and MTBVAC in the MB49 orthotopic bladder cancer mouse model, a widely used model of NMIBC which is often unresponsive to BCG, especially when intravesical treatments are delayed until three or more days after tumor cell inoculation. Interestingly, in this setting intravesical MTBVAC was capable of rejecting MB49 bladder tumors, but BCG did not. This finding correlated with an enhanced capacity of MTBVAC to colonize bladder tumors compared to BCG, a capacity which was dependent on the expression of ESAT6 and CFP10 proteins by MTBVAC which have been described to participate in adherence of mycobacteria to the epithelium and are absent in BCG. Importantly, we observed that the higher capacity of MTBVAC to colonize bladder tumors concurred with enhanced recruitment of T and NK cells to the bladder and improved tumor-specific responses.
Our results agree with a recent article also published in JITC,9 in which a recombinant BCG strain overexpressing a mannose-binding protein (FimH), displayed enhanced adhesion to the bladder epithelium and improved antitumoral potency in the orthotopic MB49 model. Therefore, although it has been long known that BCG adherence to the bladder is required for its antitumoral efficacy,10 it is only now that we are beginning to understand that improving this critical step can potentiate the antitumoral properties of live-attenuated mycobacteria.
Additionally, in our work, we observed that intravesical MTBVAC treatment strongly upregulated PD-L1 in immune cells infiltrating orthotopic bladder tumors. Given that high PD-L1 expression indicates an ongoing immune response in the tumor and is a predictor of antiPD-L1 therapy success,11 we decided to combine intravesical bacterial treatment with antiPD-L1 antibodies in the MB49 model. We delayed intravesical treatments until day 6 after tumor cell inoculation, when tumors were already fully established in the bladder. In this difficult-to-treat scenario, the MTBVAC and antiPD-L1 combination displayed a striking synergy, with 100 % of mice rejecting bladder tumors and surviving at the end of the experiment. Of note, although less effective than MTBVAC plus antiPDL1, BCG plus anti-PDL1 improved BCG or antiPD-L1 alone, showing that combinatorial treatments may be the way to go for NMIBC. Indeed, BCG combined with antiPD-L1 and radiotherapy is already being tested in clinical trials (ADAPT-BLADDER, NCT03317158).
Although these results need to be further confirmed in human clinical trials, we show that intravesical bacterial therapy for bladder cancer can be optimized by improving the intrinsic ability of the bacteria to colonize the tumor. Furthermore, potentiating bacterial therapy with immune checkpoint blockade represents a promising treatment option for BCG-unresponsive urothelial cancer.
Written by: Eduardo Moreo1,2 and Nacho Aguiló1,2
- Departamento de Microbiología, Pediatría, Radiología y Salud Pública, Universidad de Zaragoza/IIS Aragon, Zaragoza, Spain.
- CIBERES, CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
References:
- Kamat, A. M. et al. BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG. Nature Reviews Urology 14, 244–255 (2017).
- Rentsch, C. A., Hayoz, S. & Cathomas, R. Pembrolizumab monotherapy for high-risk, non-muscle-invasive bladder cancer. The Lancet Oncology 22, e379 (2021).
- Rentsch, C. A. et al. A Phase 1/2 Single-arm Clinical Trial of Recombinant Bacillus Calmette-Guérin (BCG) VPM1002BC Immunotherapy in Non–muscle-invasive Bladder Cancer Recurrence After Conventional BCG Therapy: SAKK 06/14. European Urology Oncology 5, 195–202 (2022).
- Singh, A. K. et al. Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer. Nature Communications 13, 878 (2022).
- Rentsch, C. A. et al. Bacillus Calmette-Guérin Strain Differences Have an Impact on Clinical Outcome in Bladder Cancer Immunotherapy. European Urology 66, 677–688 (2014).
- Domingos-Pereira, S. et al. Intravesical Ty21a Vaccine Promotes Dendritic Cells and T Cell–Mediated Tumor Regression in the MB49 Bladder Cancer Model. Cancer Immunology Research 7, 621–629 (2019).
- Martín, C., Marinova, D., Aguiló, N. & Gonzalo-Asensio, J. MTBVAC, a live TB vaccine poised to initiate efficacy trials 100 years after BCG. Vaccine 39, 7277–7285 (2021).
- Moreo, E. et al. Novel intravesical bacterial immunotherapy induces rejection of BCG-unresponsive established bladder tumors. Journal for ImmunoTherapy of Cancer 10, e004325 (2022).
- Zhang, Y. et al. FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer. Journal for ImmunoTherapy of Cancer 10, e003939 (2022).
- Zhao, W. et al. Role of a bacillus calmette-guerin fibronectin attachment protein in BCG-induced antitumor activity. International Journal of Cancer 86, 83–88 (2000).
- Zhou, T. C. et al. A review of the PD-1/PD-L1 checkpoint in bladder cancer: From mediator of immune escape to target for treatment. Urologic Oncology: Seminars and Original Investigations 35, 14–20 (2017).