Integrative molecular dissection of acquired resistance to PD1/PD-L1 blockade in localized and metastatic urothelial carcinoma

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Project Summary/Abstract Metastatic urothelial carcinoma (mUC) is generally incurable with modest survival benefit provided by first-line cisplatin-based chemotherapy and post-platinum PD1/L1 inhibitor therapy. Optimal therapy for progressive mUC following PD1/L1 inhibitors is necessary with new agents for this setting (enfortumab vedotin, erdafitinib) providing modest incremental benefits coupled with toxicities. Limited data exist for analysis of tumor acquired after PD1/L1 inhibitor systemic therapy, which is necessary to determine causes of both response and resistance. Indeed, multiplatform analyses of post-PD1/L1 inhibitor UC tumor have not been reported. The overarching hypothesis of this study is that tumor, immune and stromal microenvironmental factors determine resistance to PD-1/L1 therapy mUC, and that integrated bulk and single cell molecular dissection of post-treatment tumors will reveal these features. We propose innovative and potentially transformative multiplatform longitudinally obtained bulk and/or single cell (sc) analysis of pre and post PD1/L1 inhibitor tumor tissue and plasma from muscle invasive bladder cancer (MIBC) and mUC to shed deep insights regarding tumor biology and resistance and information that can be used to develop new therapies. We will perform detailed multiplatform analyses on 2 separate cohorts totaling 170 patients: 1) tumor tissue obtained before and after PD1/L1 inhibitor exposure or untreated controls (n=130) and 2) plasma cell-free (cf)-DNA obtained before and after PD1/L1 inhibitor exposure or untreated controls (n=40). Whole exome sequencing (WES), RNA-Seq and orthogonal multiparametric IHC for immune markers is performed of baseline transurethral resection of bladder tumor (TURBT) formalin fixed paraffin embedded (FFPE) specimens and post-therapy tumors. Patients included are from trials that evaluated a PD1/L1 inhibitor (n=70) as neoadjuvant therapy preceding RC for MIBC, or who received a PD1/L1 inhibitor for mUC (n=50) and control untreated and temporally separated serial FFPE tumors without intervening therapy (n=10). scRNAseq is performed on a subset of post-PD1/L1 mUC tumors (n=20) to analyze tumor, stromal and immune cells. WES is performed for immunogenomic analyses using quality-controlled plasma cfDNA obtained before and after PD1/L1 inhibitor therapy or control untreated patients (n=40). The functional relevance of specific genomic alterations and resultant predicted neoantigens is studied by examining functional immune and stromal readouts, which will shed insights regarding the immunogenicity of genomic alterations that can then provide the foundation for therapeutic advances. We will develop a novel integrated model using deep learning architecture to account for the stationary snapshot of the molecular tumor, stromal and immune profiles, and the time-based trajectory of clinical data to computationally aggregate heterogeneous data types. To summarize, this innovative study is expected to provide discoveries regarding determinants of UC progression following PD1/L1 inhibitors, an incurable disease setting with substantial unmet needs.