Imaging study offers insights on mechanism behind BCG resistance in NMIBC

In this interview, John P. Sfakianos, MD, discusses the study, “High resolution molecular imaging to elucidate the contextual mechanisms of BCG resistance in non-muscle invasive recurrent bladder cancer,” which he presented at the 2024 Bladder Cancer Advocacy Network (BCAN) Think Tank in San Diego, California. According to a news release from BCAN, the study utilized both “spatial transcriptomics and imaging mass cytometry in patient tumor samples before and after treatment with BCG to better understand BCG resistance.”¹ By doing this, investigators could assess the gene and protein activity in each sample to better understand mechanisms of BCG resistance.

John P. Sfakianos, MD

Findings from this study have led to the launch of the phase 2 ENHANCE trial (NCT06503614), which will assess the combination of durvalumab plus monalizumab in patients with BCG-unresponsive or BCG-exposed carcinoma in situ non–muscle-invasive bladder cancer (NMIBC).

Sfakianos is an associate professor of urology and urologic oncology at the Icahn School of Medicine at Mount Sinai in New York, New York.

This transcription has been edited for clarity.

Could you describe the background/rationale for conducting this research?

We've used BCG inside the bladder as the primary treatment for non-muscle invasive bladder cancer for over 30 years now. We really have yet to understand the underlying mechanism of how BCG works. But more importantly, we've not really understood how patients or the tumors themselves become resistant to BCG. So, the idea here was to use novel technologies to get a better understanding of what is happening in the tumor microenvironment to help gauge better treatments and therapies for tumors that have failed BCG therapy.

What were the findings from this study?

There are quite a few very interesting findings, both from the standpoint of the tumor and from the standpoint of the immune cells. We've focused mostly on the immune cells because that's what the lab is interested in. What we see from the immune cell standpoint specifically is that there are pockets of immune cells that are expressing immune checkpoints that are very well known to us, like PD-1. But there is also an up-regulation of a specific immune checkpoint called NKG2A, which are more specific to NK cells, but is also present on some T cells. That pathway to us is of interest because this is a pathway that can be targeted.

What future work is planned based on this study?

Interestingly, the findings from this study have already translated into an investigator-initiated clinical trial. The study is called the ENHANCE trial (NCT06503614), and it is IRB approved. ENHANCE is a phase 2 single arm clinical trial combining monalizumab and durvalumab in patients with BCG exposed and unresponsive NMIBC. So, we're combining an NKG2A inhibitor and a PD-1 inhibitor.

This is going to be a multi-institutional trial that is also being funded by BCAN and the BCAN Clinical Trial Award that we received last year for this study. The study will include both patients with carcinoma in situ that's resistant to BCG as well as papillary tumors themselves that are resistant to BCG. We're hoping to start enrolling patients in October.

What are the potential implications of this work?

The potential implications clinically would be to identify a novel treatment combination to treat patients with BCG unresponsive non-muscle invasive bladder cancer. Implications from the research perspective are important because this is a true translational project that has gone from the bench to bedside.

Reference

1. Bladder Cancer Advocacy Network announces $600,000 in funding to accelerate bladder cancer research. News release. Bladder Cancer Advocacy Network. July 11, 2022. Accessed September 22, 2024. https://bcan.org/bladder-cancer-advocacy-network-announces-600000-in-funding-to-accelerate-bladder-cancer-research/