Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance

Cancer Cell, Journal Year: 2020, Volume and Issue: 37(4), P. 471 - 484

Published: April 1, 2020

Language: Английский

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Tumour evolution in hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2019, Volume and Issue: 17(3), P. 139 - 152

Published: Dec. 2, 2019

Language: Английский

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Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Cell, Journal Year: 2021, Volume and Issue: 184(3), P. 596 - 614.e14

Published: Jan. 27, 2021

Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows clinical outcome criteria to validate multivariable predictors Clonal mutation burden (TMB) was strongest predictor response, followed by total TMB CXCL9 expression. Subclonal TMB, somatic copy alteration burden, histocompatibility leukocyte antigen (HLA) evolutionary divergence failed attain pan-cancer significance. Dinucleotide variants were identified as a source immunogenic epitopes associated with radical amino acid substitutions enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants supported prior functional evidence: 9q34 (TRAF2) loss response CCND1 amplification resistance. Finally, single-cell RNA sequencing (RNA-seq) clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined bulk RNA-seq CPI-responding tumors, CCR5 CXCL13 T-cell-intrinsic markers sensitivity.

Language: Английский

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Intratumoral heterogeneity in cancer progression and response to immunotherapy

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(2), P. 212 - 224

Published: Feb. 1, 2021

Language: Английский

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Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 5, 2021

Abstract Lung cancer is a highly heterogeneous disease. Cancer cells and within the tumor microenvironment together determine disease progression, as well response to or escape from treatment. To map cell type-specific transcriptome landscape of their in advanced non-small lung (NSCLC), we analyze 42 tissue biopsy samples stage III/IV NSCLC patients by single RNA sequencing present large scale, resolution profiles NSCLCs. In addition types described previous studies early cancer, are able identify rare tumors such follicular dendritic T helper 17 cells. Tumors different display heterogeneity cellular composition, chromosomal structure, developmental trajectory, intercellular signaling network phenotype dominance. Our study also reveals correlation with associated neutrophils, which might help shed light on function NSCLC.

Language: Английский

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Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy

Cell, Journal Year: 2021, Volume and Issue: 184(1), P. 226 - 242.e21

Published: Jan. 1, 2021

Language: Английский

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Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better?

Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 27(5), P. 1236 - 1241

Published: Nov. 16, 2020

Abstract Immune checkpoint inhibitors, including antibodies that block programmed cell death protein-1 (PD-1) and PD-L1, have transformed the management of many cancers. However, majority patients primary or acquired resistance to these immunotherapies. There is a significant unmet need for predictive biomarkers can reliably identify who derive clinically meaningful response from PD-1/PD-L1 blockade. High tumor mutational burden (TMB-H) has shown promise as biomarker in lung cancer, but broad applicability TMB-H across all solid tumors unclear. The FDA approved PD-1 inhibitor, pembrolizumab, therapy with TMB equal greater than 10 mutations/megabase measured by FoundationOne CDx assay. This approval was based on an exploratory analysis KEYNOTE-158 study, which single-arm, phase II multi-cohort study pembrolizumab select, previously treated advanced tumors. Here, we elucidate caveats using universal threshold While recognize importance this other pan-cancer approvals, several questions about remain unanswered. In perspective, discuss clinical trial evidence area. We review relationship between immune microenvironment. highlight risks extrapolating limited number histologies tumors, propose avenues future research.

Language: Английский

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Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma

Journal of Clinical Oncology, Journal Year: 2021, Volume and Issue: 39(24), P. 2656 - 2666

Published: May 12, 2021

Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in melanoma. Lifileucel is an autologous, centrally manufactured lymphocyte product.We conducted a phase II open-label, single-arm, multicenter study had been previously treated inhibitor(s) BRAF ± MEK agents. was produced from harvested tumor specimens central Good Manufacturing Practice facilities streamlined 22-day process. Patients received nonmyeloablative lymphodepletion regimen, single infusion of lifileucel, up to six doses high-dose interleukin-2. The primary end point investigator-assessed objective response rate (ORR) per RECIST, version 1.1.Sixty-six mean 3.3 prior therapies (anti-programmed death 1 [PD-1] programmed ligand [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; inhibitor: 23%). ORR 36% (95% CI, 25 49), two complete responses 22 partial responses. Disease control 80% 69 89). Median duration not reached 18.7-month median follow-up (range, 0.2-34.1 months). In the refractory anti-PD-1 PD-L1 subset, disease were 41% 26 57) 81% 66 91), respectively. Safety profile consistent known adverse events associated interleukin-2.Lifileucel durable addresses major unmet need metastatic approved therapy, including subset.

Language: Английский

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Antitumour dendritic cell vaccination in a priming and boosting approach

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 19(9), P. 635 - 652

Published: Aug. 6, 2020

Language: Английский

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Genetic and non-genetic clonal diversity in cancer evolution

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 21(6), P. 379 - 392

Published: March 16, 2021

Language: Английский

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