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IBCN 2020: Recombinant BCG Overexpressing STING Agonist Elicits Trained Immunity and Improved Antitumor Efficacy in Non-Muscle Invasive Bladder Cancer

(UroToday.com) Intravesical Bacillus Calmette–Guérin (BCG) is the first-line therapy for high-risk non-muscle-invasive bladder cancer (NIMBC). However, its mechanism of action is not fully understood. Dr. Alok Singh presented data from investigators at The Johns Hopkins University, where they have engineered a recombinant BCG (rBCG) that releases increased levels of STING agonist, c-di-AMP, and compared effects of rBCG to wild type BCG (WT-BCG) in NMIBC rat models.


Rat MNU-carcinogen model of NMIBC was used to compare antitumor efficacy of 6 weekly intravesical installations of WT-BCG versus rBCG (Figure). Compared to WT-BCG, intravesical installation of rBCG in MNU-rats resulted in significantly lower tumor involvement and more potent induction of Th1 cytokines.

Figure: In vivo experimental design and antitumor efficacy testing.

IBCN_2020_Singh.png

rBCG-treated primary human and murine macrophages showed increased IFN I, IL-6, TNF-a MCP-1 and IL-12 levels concomitant with increased M1 polarization shift. After MB49 cells were used to form flank tumors in C57Bl/6J mice, intratumoral rBCG injection caused increased tumor regression and stronger infiltration of IFN-gamma producing CD4+ T cells. The authors noted that rBCG elicited more potent epigenetic changes on TNF-alpha and IL-6 gene promoters following monocyte training.

Overall, it appears that increased proinflammatory cytokines, potentiated IFN-gamma CD4+ T cells, and increased macrophage reprogramming may contribute to enhanced antitumor efficacy of rBCG over WT-BCG in NMIBC tumor models. rBCG may therefore be a novel intravesical immunotherapeutic for patients with NMIBC.


Presented by: Alok Singh, Ph.D., The Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.

Written by: Anirban P. Mitra, MD, Ph.D., Urologic Oncology Fellow, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter: @APMitra, with Ashish M. Kamat, MD, MBBS, President of IBCN and IBCG, Endowed Professor, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter:@UroDocAsh, at the International Bladder Cancer Network (IBCN) Annual Meeting, #IBCN2020, October 17, 2020.