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Updated: Jun 28, 2026
Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Intravesical mesothelin-based CAR T cells targeting MUC16 effectively control bladder cancer in preclinical models
Parwiz Abrahimi1, Jonathan F Khan2,3,4, Alyssa Duren-Lubanski5
1Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Abstract:
Intravesical therapies are the mainstay of bladder cancer (BCa) management, but their efficacy is limited by toxicities and recurrences. While CAR T cell therapy has shown promise in hematologic malignancies, its application in solid tumors is limited by poor trafficking and on-target off-tumor toxicities. Here, we identify and validate MUC16 as a clinically relevant target for BCa, noting enriched expression in tumors recalcitrant to existing therapies. We engineered a second-generation mesothelin-based CAR (MSLN-28z) and demonstrated robust activity across multiple BCa cell lines and patient-derived tumor organoids. Intravesical delivery of MSLN-28z CAR T cells in xenograft BCa models conferred superior tumor control compared with intravenous transfer, while attenuating systemic T cell engraftment. Intravesical adoptive transfer uncouples local antitumor efficacy from potential systemic toxicity-a feature conserved across several T cell immunotherapies with on-target off-tumor activity. Collectively, these findings substantiate MUC16 as a therapeutic candidate and validate intravesical delivery as a platform for T cell immunotherapies in the management of organ-confined BCa.
Insights
Researchers identified MUC16 as a promising target for bladder cancer (BCa). Intravesical delivery of CAR T cells targeting MUC16 showed superior tumor control with reduced systemic toxicity in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Bladder cancer (BCa) treatments face challenges with toxicity and recurrence.
- CAR T cell therapy shows promise in blood cancers but struggles in solid tumors due to trafficking and toxicity issues.
Purpose of the Study:
- To identify and validate MUC16 as a therapeutic target for bladder cancer.
- To evaluate the efficacy and safety of intravesical delivery of MUC16-targeted CAR T cells for BCa treatment.
Main Methods:
- Engineered a mesothelin-based CAR (MSLN-28z) targeting MUC16.
- Tested MSLN-28z CAR T cell activity in BCa cell lines and patient-derived organoids.
- Assessed intravesical vs. intravenous delivery in xenograft BCa models.
Main Results:
- MUC16 is highly expressed in BCa, particularly in tumors resistant to current therapies.
- MSLN-28z CAR T cells demonstrated significant activity against BCa models.
- Intravesical delivery provided superior tumor control and reduced systemic T cell engraftment compared to intravenous delivery.
Conclusions:
- MUC16 is a validated therapeutic target for bladder cancer.
- Intravesical delivery of CAR T cells is a promising platform for treating organ-confined BCa, separating local efficacy from systemic toxicity.
