For patients with non-muscle-invasive bladder cancer (NMIBC) who do not respond to Bacillus Calmette-Guérin (BCG) therapy, clinicians and researchers are actively exploring novel treatment strategies. Among these, oncolytic virus therapy has emerged as a promising approach. At the 40th Annual EAU Congress, Dr. Siamak Daneshmand from the University of Southern California (USC) presented two key studies on oncolytic viruses—the BOND-003 P cohort and the PIVOT-006 trial. UroStream invited Professor Daneshmand to discuss the mechanism of action, safety, efficacy, and future directions of this innovative therapy.
UroStream:You presented two studies on cretostimogene grenadenorepvec at the conference. As an oncolytic virus specifically targeting urothelial carcinoma cells, what is its molecular mechanism?
Dr. Siamak Daneshmand：Hi everyone, this is Siamak Daneshmand from USC in Los Angeles, California. Yes, we presented two abstracts here. One was the BOND-003 study, Cohort P, which is a new cohort specifically for patients with BCG-unresponsive papillary disease. The other study was PIVOT-006.
To answer your question, Cretostimogene grenadenorepvec is a conditionally replicating oncolytic adenovirus. It targets bladder cancer cells by binding to the Coxsackie and Adenovirus Receptor (CAR), which is highly expressed on most urothelial cancer cells. This virus is engineered to encode the GM-CSF gene and works through the Rb-E2F1 pathway.
Once the virus enters the cancer cell, it replicates selectively, leading to tumor cell lysis. This process releases tumor-associated antigens, which activate the immune system and trigger a secondary immune-mediated antitumor effect. In essence, the drug operates via a dual mechanism: direct destruction of cancer cells and induction of an anti-tumor immune response.
Previous trials have already shown its clinical activity in high-grade, BCG-unresponsive NMIBC. What makes the BOND-003 Cohort P trial unique is its focus on papillary-only disease, excluding CIS, which was the main population studied in earlier trials.
UroStream:What are the efficacy and safety profiles of this drug in intermediate- and high-risk NMIBC patients?
Dr. Siamak Daneshmand：The BOND-003 trial has been running for quite some time, so we have a good understanding of the safety profile of this agent. It’s very well tolerated, with no grade 3 or 4 adverse events reported. The most common side effects are local bladder symptoms, such as dysuria, urinary frequency, and irritation—very typical of any intravesical therapy.
When it comes to efficacy in intermediate-risk patients, that’s where the PIVOT-006 trial comes in. According to the AUA classification, intermediate-risk NMIBC includes recurrent low-grade papillary tumors, tumors over 3 cm, and small high-grade Ta lesions. Although final data are still pending, we already know from earlier studies that the therapy is safe and shows promise, and the ongoing trials will help confirm its role in this broader patient population.
UroStream:Are there any predictive biomarkers (e.g., PD-L1, TMB) for the response to cretostimogene grenadenorepvec in BCG-unresponsive NMIBC?
Dr. Siamak Daneshmand：Yes, that’s the issue right now. The problem is that we don’t currently have any molecular markers that reliably tell us who will respond and who won’t. I think that’s something we really need to focus on moving forward. For now, we do know that the receptors targeted by this therapy are present in most bladder cancer cells, which explains why we’re seeing efficacy across a broad patient population. But we haven’t yet identified biomarkers that can help us determine whether this treatment—or another—would work better for an individual patient. This kind of information will be very important for future sequencing of therapies, helping us determine which patients are appropriate candidates for one option over another. It’s a critical next step in optimizing patient outcomes and personalizing care.
UroStream:What future research will you and your team pursue regarding this therapy?
Dr. Siamak Daneshmand：There’s still so much more to investigate. One of our top priorities is to understand its efficacy in low-grade disease, which is being addressed in PIVOT-006. Another area of interest is unraveling mechanisms of resistance—why some patients don’t respond, despite having the CAR receptor.
We’re also conducting several urine-based correlative studies to identify biomarkers that may predict treatment response. These studies will provide critical insights for tailoring therapy and could transform how we approach NMIBC in the near future. With every new trial and dataset, we hope to refine this therapy and offer more personalized, effective options for our patients.
