Cretostimogene Grenadenorepvec

Bladder cancer is a common malignancy in the elderly, with approximately 75% of cases diagnosed as non-muscle-invasive bladder cancer(NMIBC).Although transurethral resection of bladder tumor(TURBT)is the standard initial treatment, recurrence rates remain high, and intravesical Bacillus Calmette-Guérin(BCG)instillation has long been used as an adjuvant therapy.However, about 30% of patients develop BCG-unresponsive disease despite adequate BCG administration.Radical cystectomy is recommended in such cases, but its invasiveness and impact on quality of life(QOL)often make it impractical in real-world settings.Thus, the development of novel bladder-preserving treatments is urgently needed.In recent years, diverse approaches including immune checkpoint inhibitors(ICI), gene therapy, drug delivery systems(DDS), and oncolytic virus-based therapies have been actively investigated, with numerous clinical trials ongoing worldwide.Importantly, pembrolizumab, nadofaragene firadenovec, and N-803 in combination with BCG have received FDA approval, representing major advances in the management of BCG-unresponsive NMIBC.In addition, promising agents such as TAR-200, cretostimogene grenadenorepvec, and detalimogene voraplasmid are under clinical evaluation.These advances indicate the potential for novel strategies that enable bladder preservation while achieving tumor control.Future challenges include validation of long-term outcomes, establishment of evidence through randomized controlled trials, and regulatory approval and reimbursement in Japan.Expansion of therapeutic options is expected to improve both prognosis and QOL in this high-risk population.

Gene therapy has emerged as an attractive bladder-sparing strategy for patients with high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC), addressing a therapeutic gap for those ineligible for or declining radical cystectomy. This review aims to describe the recent advances in gene-mediated therapies for BCG-unresponsive NMIBC.

The bladder's unique anatomy with direct intravesical access and capacity for high local exposure with minimal systemic absorption provides an ideal context for gene delivery. Advances in barrier modulation with Syn3 and vector engineering have enabled efficient delivery. Adenoviral vectors as illustrated by the FDA-approved nadofaragene firadenovec (Adstiladrin), and other platforms, such as the conditionally replicating oncolytic adenoviruses (cretostimogene, CG0070), are maturing. Combination regimens of gene therapy and immune checkpoint inhibitors have shown additive or synergistic activity, deepening durability of gene therapy. Novel advancements including urinary and plasma tumor DNA are emerging as predictive biomarkers to guide patient selection, monitor minimal residual disease, and trigger early salvage.

Gene-mediated therapy is gradually advancing NMIBC care, with expanding indications and potent combinations positing itself to improve bladder preservation and long-term outcomes.