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Updated: May 2, 2026
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
Spatial comparison of molecular features associated with resistance to pembrolizumab in BCG unresponsive bladder
Khyati Meghani1, Noah Frydenlund1, Yanni Yu1
1Departments of Urology, and Biochemistry and Molecular Genetics, Feinberg School of Medicine, Chicago, Illinois, USA.
Abstract:
Intravenous immune checkpoint inhibition achieves a 40% 3-month response in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ. Yet, only half of the early responders will continue to be disease-free by 12 months, and resistance mechanisms are poorly defined. We performed spatial profiling of BCG-unresponsive tumors from patients responsive or resistant to intravenous pembrolizumab treatment, analyzing samples both before initiating and 3 months post-intravenous pembrolizumab treatment. We analyzed 119 regions of interest, which included 59 pairs of epithelial and adjacent stromal segments across five patients: two responders and three non-responders. We demonstrate that BCG unresponsive tumors with an inflamed PanCK+ tumor area and an infiltrated stromal segment respond better to intravenous pembrolizumab. Furthermore, using segment-specific gene signatures generated from a cohort of BCG unresponsive NMIBC treated with intravesical BCG+pembrolizumab, we find that non-inflamed, immune-cold tumors that do not respond to intravenous pembrolizumab exhibit a favorable outcome to the combined application of BCG and pembrolizumab. For the first time, we have identified molecular features of tumors associated with response and resistance to intravenous pembrolizumab in BCG unresponsive NMIBCs. Further research with more patients and alternative checkpoint inhibitors is essential to validate our findings. We anticipate that using a transcriptomics signature like the one described here can help identify tumors with a higher possibility of responding to intravenous pembrolizumab.
Insights
Intravenous pembrolizumab shows promise for BCG-unresponsive bladder cancer, but resistance is common. Inflamed tumors respond better, while immune-cold tumors may benefit from combined BCG and pembrolizumab therapy.
Area of Science:
- Oncology
- Immunology
- Urology
Background:
- Intravenous immune checkpoint inhibitors (ICIs) demonstrate a 40% response rate at 3 months for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ.
- However, sustained disease-free survival beyond 12 months is limited in approximately half of responders, and resistance mechanisms remain poorly understood.
Purpose of the Study:
- To investigate the molecular features associated with response and resistance to intravenous pembrolizumab in BCG-unresponsive NMIBC.
- To identify potential biomarkers for predicting treatment outcomes and guiding therapeutic strategies.
Main Methods:
- Spatial profiling was conducted on tumor samples from five patients (two responders, three non-responders) with BCG-unresponsive NMIBC before and 3 months after intravenous pembrolizumab treatment.
- Analysis included 119 regions of interest, comprising 59 epithelial and adjacent stromal segments.
- Segment-specific gene signatures were generated from a cohort of NMIBC patients treated with intravesical BCG plus pembrolizumab.
Main Results:
- BCG-unresponsive tumors with an inflamed PanCK+ area and infiltrated stroma showed a better response to intravenous pembrolizumab.
- Immune-cold tumors, identified through gene signatures, that did not respond to intravenous pembrolizumab demonstrated a favorable outcome with combined intravesical BCG and pembrolizumab therapy.
Conclusions:
- This study identifies, for the first time, molecular features linked to response and resistance to intravenous pembrolizumab in BCG-unresponsive NMIBC.
- Transcriptomic signatures may aid in selecting patients likely to respond to pembrolizumab, while combined BCG and ICI therapy presents an alternative for non-inflamed tumors.
- Further validation with larger patient cohorts and diverse checkpoint inhibitors is crucial.
