Personalized Intravesical Immunotherapy for Bladder Cancer
Restricted (Penn State Only)
- Author:
- Yan, Yue
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 13, 2024
- Committee Members:
- Daniel Hayes, Program Head/Chair
David Degraff, Outside Unit & Field Member
Pak Kin Wong, Chair & Dissertation Advisor
Yong Wang, Major Field Member
Justin Pritchard, Major Field Member
Yuguo Lei, Major Field Member - Keywords:
- cancer
bladder cancer
immunotherapy
cancer immunotherapy
personalized medicine - Abstract:
- Bladder cancer ranks as the sixth most prevalent cancer, with an annual incidence exceeding 80,000 cases in the United States. Notably, approximately 75% of these cases are high-risk non-muscle invasive bladder cancer (NMIBC). The standard therapeutic approach involves intravesical microbiome-based immunotherapy using Bacillus Calmette–Guérin (BCG). However, approximately 40% of patients exhibit BCG treatment failure, leading to a high risk of recurrence and progression to muscle-invasive bladder cancer (MIBC). Therefore, we have developed an innovative alternative to BCG, utilizing personalized cocktails of microbial products for intravesical microbiome-based immunotherapy. Our approach includes a microfluidic platform employing comparative assays to predict the efficacy of microbiome-based immunotherapy, allowing for detailed analysis of immune-tumor interactions. This phenotypic assay, when used in conjunction with existing genotypic and proteomic analyses, has the potential to significantly enhance the precision of efficacy predictions in clinical settings, providing uniquely clear and direct insights into the treatment's impact. Furthermore, we employed an AI-assisted workflow integrating experimental approaches and a neural network regression model to identify effective microbial product cocktails (MPCs). These cocktails were subsequently subjected to the phenotypic assay using patient-derived organoids from transurethral resection of bladder tumors (TURBT). Finally, we demonstrated the effectiveness of these microbial cocktails in an in vivo orthotopic mouse model, showing improved immune infiltration and doubled long-term survival rates compared to BCG. Our study reveals that these personalized MPCs offer a promising new treatment avenue for high-risk non-muscle invasive bladder cancer, potentially outperforming the standard BCG therapy and heralding a new era in the management of the disease.