The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

Cancer Cell, Journal Year: 2020, Volume and Issue: 39(2), P. 154 - 173

Published: Oct. 30, 2020

Language: Английский

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Next generation of immune checkpoint therapy in cancer: new developments and challenges

Journal of Hematology & Oncology, Journal Year: 2018, Volume and Issue: 11(1)

Published: March 15, 2018

Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance assist with immune response. In cancer, checkpoint are often activated to inhibit the nascent anti-tumor therapies act by blocking or stimulating these enhance body’s immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), ligand-1(PD-L1) most widely studied recognized pathways. Drugs currently utilized for a wide variety malignancies have demonstrated durable clinical activities in subset cancer patients. This approach is rapidly extending beyond CTLA-4 PD-1/PD-L1. New under investigation, drugs LAG-3, TIM-3, TIGIT, VISTA, B7/H3 being investigated. Furthermore, agonists such as OX40, ICOS, GITR, 4-1BB, CD40, molecules targeting tumor microenvironment components like IDO TLR investigation. this article, we provided comprehensive review involved immunotherapy, discuss their mechanisms therapeutic interventions investigation phase I/II trials. We also reviewed limitations, toxicities, challenges outline possible future research directions.

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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Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

Nature, Journal Year: 2023, Volume and Issue: 618(7963), P. 144 - 150

Published: May 10, 2023

Abstract Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients 1 , yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3 . Here a phase I trial adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA real time from surgically resected PDAC tumours. After surgery, sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), cevumeran (a maximum 20 per patient) and modified version four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan oxaliplatin). The end points included vaccine-induced neoantigen-specific cells by high-threshold assays, 18-month recurrence-free survival oncologic feasibility. We treated 16 with then 15 mFOLFIRINOX. Autogene was within 3 days benchmarked times, tolerable induced de novo high-magnitude 8 out patients, half targeting more than one neoantigen. Using new mathematical strategy to track clones (CloneTrack) functional found vaccine-expanded comprised up 10% all blood cells, re-expanded booster long-lived polyfunctional effector CD8 + cells. At median follow-up, (responders) had longer (not reached) compared without (non-responders; 13.4 months, P = 0.003). Differences the immune fitness did not confound this correlation, as responders non-responders mounted equivalent immunity concurrent unrelated against SARS-CoV-2. Thus, atezolizumab, mFOLFIRINOX induces substantial activity may correlate delayed recurrence.

Language: Английский

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A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma

Nature Medicine, Journal Year: 2019, Volume and Issue: 25(3), P. 454 - 461

Published: Feb. 25, 2019

Language: Английский

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Mechanisms of immunotherapy resistance: lessons from glioblastoma

Nature Immunology, Journal Year: 2019, Volume and Issue: 20(9), P. 1100 - 1109

Published: July 29, 2019

Language: Английский

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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

Cell, Journal Year: 2020, Volume and Issue: 183(2), P. 347 - 362.e24

Published: Oct. 1, 2020

Language: Английский

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The hallmarks of successful anticancer immunotherapy

Science Translational Medicine, Journal Year: 2018, Volume and Issue: 10(459)

Published: Sept. 19, 2018

Various features of the tumor and immune system influence success immunotherapy.

Language: Английский

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Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside

Trends in cancer, Journal Year: 2018, Volume and Issue: 4(4), P. 292 - 319

Published: March 18, 2018

Language: Английский

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Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies

Cancer Cell, Journal Year: 2018, Volume and Issue: 33(4), P. 581 - 598

Published: April 1, 2018

Language: Английский

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