Scientists at UC San Francisco have made a breakthrough in treating one of the most challenging forms of bladder cancer, developing a targeted immunotherapy for histologic variant (HV) bladder cancer that affects up to 25% of all bladder cancer cases. The research, published June 17 in Nature Communications and funded by the National Institutes of Health, offers new hope for patients with tumors that have historically been excluded from clinical trials.
Novel Biomarkers Identified in Aggressive Bladder Cancer
Unlike conventional bladder cancer, which exhibits predictable characteristics and responds to established treatments, HV bladder tumors display bewildering morphological variations and resist standard chemotherapy and immunotherapy. These aggressive cancers leave radical surgery as the primary treatment option, yet recurrence rates remain alarmingly high.
Using advanced single-cell sequencing technology developed in-house, UCSF researchers analyzed gene expression in individual tumor cells from both conventional and HV bladder tumors. The analysis revealed that most HV tumors, regardless of subtype, expressed CA125 - a carbohydrate antigen previously associated only with ovarian cancer. Conventional bladder tumors notably lacked these CA125-expressing cells.
"Our lab's single cell sequencing technology enabled us to go from patient biopsies to laboratory testing and back to a promising therapy in just a few years," said Franklin Huang, MD, PhD, an oncologist and professor of medicine and urology at UCSF who co-authored the study.
CAR-T Therapy Shows Promise in Preclinical Models
The researchers also discovered that HV tumors consistently expressed TM4SF1, a transmembrane protein on their cell surfaces. This protein emerged as a promising target for immunotherapeutic intervention, leading the team to develop chimeric antigen receptor T-cell (CAR-T) therapy specifically engineered to target TM4SF1-expressing tumor cells.
In preclinical testing, the engineered CAR-T cells demonstrated remarkable efficacy in mouse models. The immune cells successfully tracked down bladder tumors and destroyed them with precision, providing compelling evidence that this targeted immunotherapy could overcome traditional barriers posed by tumor heterogeneity.
Addressing an Unmet Medical Need
The discovery addresses a critical gap in bladder cancer treatment. HV tumors are often excluded from clinical trials due to their diverse appearances, preventing the development of new therapies for this patient population.
"Far too often, however, these tumors grow back," noted Sima Porten, MD, associate professor of urology at UCSF and co-senior author of the study. "The discovery holds immense promise for patients. HV tumors are often excluded from clinical trials due to their diverse appearances, precluding the development of new therapies."
Implications for Precision Medicine
The research represents a significant advancement in precision oncology, demonstrating how sophisticated genomic tools can uncover therapeutic targets in previously untreatable cancers. The ability to stratify patients based on molecular profiles like CA125 and TM4SF1 expression could refine clinical trial designs and enable more inclusive studies for this neglected patient population.
The multidisciplinary collaboration spanning urology, oncology, genomics, and immunotherapy was supported by funding from the National Institutes of Health, Chan-Zuckerberg Biohub, and dedicated urology foundations. This support underscores the importance of fostering innovative cancer research infrastructure capable of bridging fundamental science and clinical application.
Path Forward
While the preclinical success of TM4SF1-targeted CAR-T therapy is promising, future studies will need to address therapeutic safety, efficacy in human subjects, potential off-target effects, and durability of anti-tumor responses. The research team believes this approach could finally move the needle for patients with HV bladder cancer, who typically have very few treatment options.
"We think this could finally move the needle for patients with HV bladder cancer, who typically have very few options for treatment," Huang emphasized, highlighting the potential to transform what is often a fatal diagnosis into a manageable condition.
