PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer

Breast Care, Journal Year: 2016, Volume and Issue: 11(6), P. 385 - 390

Published: Jan. 1, 2016

Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity may lead to durable long-term disease control, especially triple-negative subtypes cancer (TNBC). Although immune blockade is generally well tolerated, specific immune-related adverse events (irAEs) occur. This review summarizes clinical efficacy, perspectives, future challenges using PD-1/PD-L1-directed antibodies

Language: Английский

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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 372(26), P. 2509 - 2520

Published: May 30, 2015

Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic due mismatch-repair defects may be susceptible immune checkpoint blockade.We conducted phase 2 study evaluate clinical activity pembrolizumab, an anti-programmed death 1 inhibitor, in 41 patients progressive metastatic carcinoma or without deficiency. Pembrolizumab was administered intravenously at dose 10 mg per kilogram body weight every 14 days mismatch repair-deficient colorectal cancers, repair-proficient and cancers were not colorectal. The coprimary end points immune-related objective response rate 20-week progression-free survival rate.The 40% (4 patients) 78% (7 9 patients), respectively, for 0% (0 18 11% (2 cancers. median overall reached cohort cancer but 2.2 5.0 months, (hazard ratio disease progression death, 0.10 [P<0.001], hazard 0.22 [P=0.05]). Patients noncolorectal had responses similar those (immune-related rate, 71% [5 7 patients]; 67% [4 6 patients]). Whole-exome sequencing revealed mean 1782 tumor tumors, as compared 73 (P=0.007), high mutation loads associated prolonged (P=0.02).This showed status predicted benefit blockade pembrolizumab. (Funded by Johns Hopkins University others; ClinicalTrials.gov number, NCT01876511.).

Language: Английский

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Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 373(2), P. 123 - 135

Published: May 31, 2015

Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared docetaxel in this patient population.We randomly assigned 272 patients to receive at dose mg per kilogram body weight every 2 weeks, docetaxel, 75 square meter body-surface area weeks. The primary end point was overall survival.The median survival 9.2 months (95% confidence interval [CI], 7.3 13.3) nivolumab versus 6.0 CI, 5.1 7.3) docetaxel. risk 41% lower than (hazard ratio, 0.59; 95% 0.44 0.79; P<0.001). At year, rate 42% 34 50) 24% 17 31) response 20% 9% (P=0.008). progression-free 3.5 2.8 ratio for progression, 0.62; 0.47 0.81; expression PD-1 ligand (PD-L1) neither prognostic nor predictive benefit. Treatment-related adverse events grade 4 were reported 7% group 55% those group.Among advanced, previously treated NSCLC, survival, rate, significantly better regardless PD-L1 level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).

Language: Английский

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Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Science, Journal Year: 2015, Volume and Issue: 348(6230), P. 124 - 128

Published: March 13, 2015

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response this therapy, we used whole-exome sequencing non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated molecular smoking signature, neoantigen burden, DNA repair pathway mutations; each factor burden. one responder, neoantigen-specific CD8+ responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances reactivity. Our results suggest landscape shapes therapy.

Language: Английский

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Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial

The Lancet, Journal Year: 2015, Volume and Issue: 387(10027), P. 1540 - 1550

Published: Dec. 19, 2015

Language: Английский

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Science, Journal Year: 2017, Volume and Issue: 357(6349), P. 409 - 413

Published: July 27, 2017

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers somatic mutations. In a proof-of-concept study, we previously showed that colorectal with deficiency were sensitive to immune checkpoint blockade antibodies programmed death receptor-1 (PD-1). We have now expanded this study evaluate the efficacy PD-1 patients advanced repair-deficient across 12 different tumor types. Objective radiographic responses observed 53% patients, and complete achieved 21% patients. Responses durable, median progression-free survival overall still not reached. Functional analysis responding patient demonstrated rapid vivo expansion neoantigen-specific T cell clones reactive mutant neopeptides found tumor. These data support hypothesis large proportion neoantigens make them blockade, regardless cancers' tissue origin.

Language: Английский

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Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 372(21), P. 2018 - 2028

Published: April 19, 2015

We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients advanced non–small-cell lung cancer enrolled a phase study. also sought to define validate an expression level PD-1 ligand (PD-L1) that is associated likelihood clinical benefit.

Language: Английский

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Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

New England Journal of Medicine, Journal Year: 2020, Volume and Issue: 382(20), P. 1894 - 1905

Published: May 13, 2020

The combination of atezolizumab and bevacizumab showed encouraging antitumor activity safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.

Language: Английский

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Understanding the tumor immune microenvironment (TIME) for effective therapy

Nature Medicine, Journal Year: 2018, Volume and Issue: 24(5), P. 541 - 550

Published: April 20, 2018

Language: Английский

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Elements of cancer immunity and the cancer–immune set point

Nature, Journal Year: 2017, Volume and Issue: 541(7637), P. 321 - 330

Published: Jan. 1, 2017

Language: Английский

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