scholarly journals Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

2021 ◽  
Vol 9 (10) ◽  
pp. e003001
Author(s):  
Amy A Lo ◽  
Andrew Wallace ◽  
Daniel Oreper ◽  
Nicolas Lounsbury ◽  
Charles Havnar ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Case ◽  
Tumor Evolution ◽  
Tumor Type ◽  
Specific Tumor ◽  
Bladder Cancer Case ◽  
Cancer Types ◽  
Cancer Cell Fraction ◽  
Cancer Immunotherapies ◽  
Single Tumor

BackgroundIndividualized neoantigen-specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. It is assumed that clonal neoantigens are preferred targets for immunotherapy, but the distributions of clonal neoantigens are not well characterized across cancer types.MethodsWe combined multiregion sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients in order to characterize their globally clonal neoantigen content and factors that would impact neoantigen targeting.ResultsBranching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. In colorectal, renal, and bladder cancer, most tumors had few globally clonal neoantigens. Prioritizing mutations with higher purity-adjusted and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases.ConclusionsWe show that tumor type, multilesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection, and may also be important factors to consider in the development of biomarker strategies.

scholarly journals Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

2021 ◽  
Author(s):  
Amy A. Lo ◽  
Andrew Wallace ◽  
Daniel Oreper ◽  
Nicolas Lounsbury ◽  
Charles Havnar ◽  
...  
Keyword(s):  
Specific Immunotherapy ◽  
Cancer Case ◽  
Tumor Evolution ◽  
Small Cell Lung ◽  
Variant Allele Frequency ◽  
Specific Tumor ◽  
Bladder Cancer Case ◽  
Cancer Cell Fraction ◽  
Cancer Immunotherapies ◽  
Single Tumor

Individualized neoantigen specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. To characterize these potential obstacles, we combined multi-region sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients. Branching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. Prioritizing mutations with higher purity- and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases. Our results show that indication type, multi-lesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection.

Granulomatous Hepatitis as a Rare Complication of Intravesical BCG Therapy for Bladder Cancer: Case Report

2010 ◽  
Vol 30 (3) ◽  
pp. 1092-1095
Author(s):  
İbrahim Koral ÖNAL ◽  
Meral AKDOĞAN ◽  
Adalet AYPAK ◽  
Perihan OĞUZ ◽  
Tülay TEMUÇİN KEKLİK ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Case Report ◽  
Rare Complication ◽  
Cancer Case ◽  
Granulomatous Hepatitis ◽  
Bcg Therapy ◽  
Intravesical Bcg ◽  
Bladder Cancer Case ◽  
Intravesical Bcg Therapy

CSF producing gall bladder cancer: Case report and characteristics of the csf produced by tumor cells

1985 ◽  
Vol 3 (5) ◽  
pp. 294-303 ◽  
Author(s):  
Masuhiro Takahashi ◽  
Masahiro Fujiwam ◽  
Kenji Kishi ◽  
Chikara Sakai ◽  
Masayoshi Sad ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Case Report ◽  
Gall Bladder ◽  
Tumor Cells ◽  
Gall Bladder Cancer ◽  
Cancer Case ◽  
Bladder Cancer Case

scholarly journals Risk of Alcohol Consumption in Bladder Cancer: Case-Control Study from a Nationwide Inpatient Database in Japan

2016 ◽  
Vol 239 (1) ◽  
pp. 9-15 ◽  
Author(s):  
Masayoshi Zaitsu ◽  
Fumiaki Nakamura ◽  
Satoshi Toyokawa ◽  
Akiko Tonooka ◽  
Takumi Takeuchi ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Alcohol Consumption ◽  
Case Control Study ◽  
Case Control ◽  
Cancer Case ◽  
Bladder Cancer Case ◽  
Inpatient Database ◽  
Control Study

scholarly journals Bayesian inference of cancer driver genes using signatures of positive selection

2017 ◽  
Author(s):  
Luis Zapata ◽  
Hana Susak ◽  
Oliver Drechsel ◽  
Marc R. Friedländer ◽  
Xavier Estivill ◽  
...  
Keyword(s):  
Bayesian Inference ◽  
Large Fraction ◽  
Driver Gene ◽  
Tumor Type ◽  
Sequencing Data ◽  
Cancer Etiology ◽  
Driver Genes ◽  
Cancer Driver ◽  
Cancer Types ◽  
Cancer Cell Fraction

AbstractTumors are composed of an evolving population of cells subjected to tissue-specific selection, which fuels tumor heterogeneity and ultimately complicates cancer driver gene identification. Here, we integrate cancer cell fraction, population recurrence, and functional impact of somatic mutations as signatures of selection into a Bayesian inference model for driver prediction. In an in-depth benchmark, we demonstrate that our model, cDriver, outperforms competing methods when analyzing solid tumors, hematological malignancies, and pan-cancer datasets. Applying cDriver to exome sequencing data of 21 cancer types from 6,870 individuals revealed 98 unreported tumor type-driver gene connections. These novel connections are highly enriched for chromatin-modifying proteins, hinting at a universal role of chromatin regulation in cancer etiology. Although infrequently mutated as single genes, we show that chromatin modifiers are altered in a large fraction of cancer patients. In summary, we demonstrate that integration of evolutionary signatures is key for identifying mutational driver genes, thereby facilitating the discovery of novel therapeutic targets for cancer treatment.

Transrectal Radiofrequency Ablation for Pelvic Recurrence of Bladder Cancer: Case Report and Review of Complications

2005 ◽  
Vol 16 (7) ◽  
pp. 1027-1032 ◽  
Author(s):  
Craig Campbell ◽  
Michael C. Soulen ◽  
Stephen C. Horii ◽  
Evan S. Seigelman ◽  
Stephen E. Rubesin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Case Report ◽  
Radiofrequency Ablation ◽  
Pelvic Recurrence ◽  
Cancer Case ◽  
Bladder Cancer Case

scholarly journals 93 Computational biology and tissue-based approaches to inform indication selection for a novel AHR inhibitor

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A102-A102
Author(s):  
Marta Sanchez-Martin ◽  
Lei Wang ◽  
Jeffrey Ecsedy ◽  
Karen Mcgovern ◽  
Michelle Zhang
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Protein Detection ◽  
Transcriptional Analysis ◽  
Tumor Type ◽  
Aryl Hydrocarbon ◽  
Pathway Activation ◽  
Cancer Types ◽  
Ahr Gene

BackgroundAryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activities of multiple innate and adaptive immune cell types. Multiple ligands such as kynurenine bind to AHR driving its nuclear translocation and transcriptional activation, leading to an immunosuppressive tumor microenvironment.1 2 AHR activation is implicated in tumor development in multiple cancer types. In addition, high levels of serum kynurenine are associated with resistance to checkpoint inhibitors.3 To overcome AHR-mediated immunosuppression in cancers, we developed a selective oral AHR inhibitor IK-175 and took a combined computational and tissue-based approach to select cancer indications for its clinical development.MethodsThe aim of this work is to identify tumor indications dependent on AHR signaling and design patient selection strategies based on a proprietary transcriptional signature, mRNA and protein detection assays to evaluate AHR pathway activation in tumors.ResultsGenomic profiling of solid and hematological cancers from TCGA and Project GENIE databases identified bladder and esophageal tumors among others, as frequently harboring AHR gene amplifications.A proprietary gene signature of AHR activation was developed integrating literature, pathway analysis, RNAseq and nanostring data from PBMC, T-cells and cell lines upon AHR inhibition. Transcriptional analysis of the TCGA data using this signature demonstrated bladder cancer has the highest expressions of AHR and AHR signature genes, suggesting increased pathway activity in bladder cancer relative to other cancer types. Increased AHR signature gene expression was associated with worse overall survival in the TCGA bladder cancer cohort. Furthermore, RNAscope analysis of a tissue microarray containing 10 different tumor types revealed bladder cancer had one of the highest AHR transcript expression in the tumor compartment.Finally, nuclear localization of AHR protein was assessed as an indicator of pathway activation through the development of a novel IHC method. Extensive TMA screening of AHR protein in 15 different indications demonstrated bladder cancer as the tumor type with the highest prevalence of AHR nuclear expression.ConclusionsIn summary, we demonstrated high prevalence of nuclear AHR protein expression, AHR gene amplification and target gene expression in bladder cancer, suggesting aberrant AHR activation may play an important role in the progression of this tumor type. This study provides rationale for therapeutic targeting of AHR in bladder cancer patients. Ikena is currently evaluating the anti-tumor activity of IK-175 as a single agent and in combination with nivolumab in bladder cancer in a Phase 1a/1b clinical study (NCT04200963).ReferencesQuintana FJ, Sherr DH. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 2013 Aug 1;65(4):1148–61.Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014 Dec;14(12):801–14.Li, Haoxin et al. ‘Metabolomic adaptations and correlates of survival to immune checkpoint blockade.’ Nature Communications 2019 Sep 25;10:1–4346.

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