An innovative imaging study has shed light on the mechanisms driving resistance to Bacillus Calmette-Guérin (BCG) therapy in patients with non-muscle invasive bladder cancer (NMIBC), potentially paving the way for more effective treatment strategies. The research, presented at the 2024 Bladder Cancer Advocacy Network (BCAN) Think Tank, utilized spatial transcriptomics and imaging mass cytometry to analyze tumor samples before and after BCG treatment.
Unraveling BCG Resistance
For over three decades, BCG has been the primary intravesical treatment for NMIBC. However, the underlying mechanisms of its action and the development of resistance remain poorly understood. According to John P. Sfakianos, MD, an associate professor of urology and urologic oncology at the Icahn School of Medicine at Mount Sinai, the study aimed to use novel technologies to gain a better understanding of the tumor microenvironment and identify potential therapeutic targets for BCG-resistant tumors.
The study's findings revealed that in BCG-resistant tumors, immune cells exhibit upregulation of immune checkpoints, including PD-1 and, notably, NKG2A. NKG2A, primarily associated with NK cells but also present on some T cells, presents a particularly attractive target due to the availability of inhibitors.
ENHANCE Trial: A New Therapeutic Approach
The insights gained from this study have directly translated into the ENHANCE trial (NCT06503614), a phase 2 single-arm clinical trial. This trial will evaluate the combination of monalizumab, an NKG2A inhibitor, and durvalumab, a PD-1 inhibitor, in patients with BCG-exposed and unresponsive NMIBC. The trial is investigator-initiated and IRB approved.
The ENHANCE trial, funded in part by a BCAN Clinical Trial Award, will be a multi-institutional effort. It will include patients with both carcinoma in situ and papillary tumors resistant to BCG. Enrollment is anticipated to begin in October.
"We're combining an NKG2A inhibitor and a PD-1 inhibitor," Dr. Sfakianos explained, highlighting the rationale behind the therapeutic approach. By targeting both PD-1 and NKG2A, the researchers aim to overcome immune evasion mechanisms and enhance the anti-tumor immune response in patients who have failed BCG therapy.
