The Role of Interferon in the Management of BCG Refractory Nonmuscle Invasive Bladder Cancer

Correa, Andres; Theisen, Katherine M.; Ferroni, Matthew C.; Maranchie, Jodi K.; Hrebinko, Ronald L.; Davies, Ben; Gingrich, Jeffrey R.

doi:10.1155/2015/656918

Cited by 10 publications

(2 citation statements)

References 27 publications

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“…A primary goal of this study was to determine whether the antitumor efficacy of BCG in urothelial cancer models could be enhanced by engineering excess production of the STING agonist, c-di-AMP. In light of studies showing elevated Type I IFN and NF-κB-mediated antitumor host immune responses in NMIBC patients who respond to BCG [55][56][57] , we reasoned that adding STING agonist overexpression to traditional BCG might further increase these favorable immune parameters. c-di-AMP is a STING agonist produced naturally in low levels by BCG (where it serves as a second messenger signaling molecule in microbial physiology), that is closely related to the natural human STING ligand, cGAMP 58,59 .…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Singh

Praharaj

Lombardo

et al. 2020

Preprint

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BCG remains first-line therapy for non-muscle invasive bladder cancer (NIMBC) but its mechanism of action is not fully understood. We developed a recombinant BCG (rBCG) that releases the STING agonist, c-di-AMP. Compared with BCG, rBCG demonstrated superior antitumor efficacy in models of NMIBC, more potent pro-inflammatory cytokine responses, greater myeloid cell reprogramming (M1 shift) and enhanced epigenetic and metabolomic changes favoring antitumor immunity. These findings are signatures of trained immunity and reveal that STING pathway activation is a proximal trigger in trained immunity remodeling. Trained immunity may be a central mechanism for both BCG and rBCG antitumor activity in NMIBC. INTRODUCTION:Bacillus Calmette-Guérin (BCG)--the only FDA-approved bacterial agent for cancer immunotherapy--has been in use for the treatment of high-risk non-muscle invasive bladder cancer (NMIBC) as a first-line therapy since the late 1970s. More than one-third of patient's with NMIBC will experience tumor recurrence after receiving BCG, and these patients have limited options other than removal of the bladder and creation of a urinary diversion -a major life-altering event. Thus, there is a significant unmet need for improved versions of BCG that provide superior response rates and prevent disease progression 1 . At the current time intravesical options for bladder preserving therapy remain limited.Following bladder instillation, BCG induces a local inflammatory response accompanied by infiltration of granulocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs), and CD4 + and CD8 + T cells, accompanied by release of pro-inflammatory cytokines including IL-6, TNF-a, and IFN-g 2-7 . However, the specific immune mechanisms leading to BCG-mediated tumor eradication as well as BCG-resistance are not well-understood. BCG has been found to impart potent heterologous protection against non-related viral and bacterial infections; it elicits this protection via an innate immune memory mechanism known as trained immunity 8-11 . Trained immunity is characterized by metabolic, epigenetic and transcriptional reprogramming of both myeloid and lymphoid lineages 12-15 but it has not been extensively studied as an antitumor mechanism during BCG immunotherapy for NMIBC.Recent studies have implicated the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signaling effector, stimulator of interferon genes (STING), in a key immune response pathway known as the cytosolic surveillance pathway (CSP), which responds to DNA and cyclic dinucleotides aberrantly present in the cytosol [16][17][18][19] . Activated cGAS catalyzes the formation of 2′3′-cGAMP, a cyclic dinucleotide (CDN) that is a potent STING agonist.Activation of STING leads to stimulation of Type I interferon and NF-κB-mediated immune responses, including elevated dendritic cell priming and T-effector (Teff) cell recruitment 20-23 . 4Small molecule STING agonists elicit potent pro-inflammatory responses, and correspondingly have shown signific...

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Singh

Praharaj

Lombardo

et al. 2020

Preprint

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“…10 Patients who failed BCG treatment were treated with IFN and BCG in lower doses than the conventional protocols for BCG alone. 11,12 In a study with 236 patients with frequently recurring Ta or T1 Grade 1-2 NMIBC, treated with mitomycin C instillations followed by monthly BCG, significantly reduced long-term disease recurrence in relation to alternating instillations of BCG and IFN-α2b. Therefore, the combined therapy of BCG with IFN-α offers an appreciable clinical benefit compared with BCG alone.…”

Section: Immunomodulatorsmentioning

confidence: 99%

Advances and Perspectives in Urinary Bladder Cancer Nanotherapy

et al. 2018

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Bladder cancer treatment remains a challenge in the pharmaceutical field due to the recurrence and progression of the disease, as well as the pronounced side effects associated with the available therapeutic modalities. Although important strategies have been investigated in different clinical trial phases, efficient and well-tolerated treatment approaches need to be developed to improve therapeutic efficacy and the quality of life for bladder cancer patients. This review discusses conventional protocols used in the clinical setting, detailing the use of Bacillus Calmette–Guérin, new immunomodulators, and drug delivery systems. New therapeutic approaches have been investigated with the aim of better therapeutic efficacy with low rates of recurrence and progression of non-muscle invasive bladder cancer and muscle invasive bladder cancer. Therefore, this review highlights the progression of therapy with the use of conventional treatments and the recent progress achieved from the use of innovative strategies, such as nanoparticles for sustained, controlled drug delivery and increased drug uptake by tumour cells.

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