Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.
Robertson A Gordon,Kim Jaegil,Al-Ahmadie Hikmat,Bellmunt Joaquim,Guo Guangwu,Cherniack Andrew D,Hinoue Toshinori,Laird Peter W,Hoadley Katherine A,Akbani Rehan,Castro Mauro A A,Gibb Ewan A,Kanchi Rupa S,Gordenin Dmitry A,Shukla Sachet A,Sanchez-Vega Francisco,Hansel Donna E,Czerniak Bogdan A,Reuter Victor E,Su Xiaoping,de Sa Carvalho Benilton,Chagas Vinicius S,Mungall Karen L,Sadeghi Sara,Pedamallu Chandra Sekhar,Lu Yiling,Klimczak Leszek J,Zhang Jiexin,Choo Caleb,Ojesina Akinyemi I,Bullman Susan,Leraas Kristen M,Lichtenberg Tara M,Wu Catherine J,Schultz Nicholaus,Getz Gad,Meyerson Matthew,Mills Gordon B,McConkey David J, ,Weinstein John N,Kwiatkowski David J,Lerner Seth P
We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer.
Lee Suk Hyung,Hu Wenhuo,Matulay Justin T,Silva Mark V,Owczarek Tomasz B,Kim Kwanghee,Chua Chee Wai,Barlow LaMont J,Kandoth Cyriac,Williams Alanna B,Bergren Sarah K,Pietzak Eugene J,Anderson Christopher B,Benson Mitchell C,Coleman Jonathan A,Taylor Barry S,Abate-Shen Cory,McKiernan James M,Al-Ahmadie Hikmat,Solit David B,Shen Michael M
Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
Intratumoral CD4 T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer.
Oh David Y,Kwek Serena S,Raju Siddharth S,Li Tony,McCarthy Elizabeth,Chow Eric,Aran Dvir,Ilano Arielle,Pai Chien-Chun Steven,Rancan Chiara,Allaire Kathryn,Burra Arun,Sun Yang,Spitzer Matthew H,Mangul Serghei,Porten Sima,Meng Maxwell V,Friedlander Terence W,Ye Chun Jimmie,Fong Lawrence
Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8 T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4 T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4 T cell states that are clonally expanded. These CD4 T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4 T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.
A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer.
Ott Patrick A,Hu-Lieskovan Siwen,Chmielowski Bartosz,Govindan Ramaswamy,Naing Aung,Bhardwaj Nina,Margolin Kim,Awad Mark M,Hellmann Matthew D,Lin Jessica J,Friedlander Terence,Bushway Meghan E,Balogh Kristen N,Sciuto Tracey E,Kohler Victoria,Turnbull Samantha J,Besada Rana,Curran Riley R,Trapp Benjamin,Scherer Julian,Poran Asaf,Harjanto Dewi,Barthelme Dominik,Ting Ying Sonia,Dong Jesse Z,Ware Yvonne,Huang Yuting,Huang Zhengping,Wanamaker Amy,Cleary Lisa D,Moles Melissa A,Manson Kelledy,Greshock Joel,Khondker Zakaria S,Fritsch Ed,Rooney Michael S,DeMario Mark,Gaynor Richard B,Srinivasan Lakshmi
Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4 and CD8 T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).