Cancer immunotherapy using checkpoint blockade

Science, Год журнала: 2018, Номер 359(6382), С. 1350 - 1355

Опубликована: Март 22, 2018

The release of negative regulators immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates long-lasting tumor patients with a variety cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or programmed cell death 1 (PD-1) pathway, either alone combination. main premise for inducing an response is preexistence cells were limited specific checkpoints. Most who have maintain disease control, yet one-third relapse. Mechanisms acquired resistance are currently poorly understood, but evidence points to alterations converge on antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome mechanisms checkpoint therapy.

Язык: Английский

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Colorectal cancer

The Lancet, Год журнала: 2019, Номер 394(10207), С. 1467 - 1480

Опубликована: Окт. 1, 2019

Язык: Английский

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Tumor Mutational Burden and Response Rate to PD-1 Inhibition

New England Journal of Medicine, Год журнала: 2017, Номер 377(25), С. 2500 - 2501

Опубликована: Дек. 20, 2017

In a survey of the spectrum mutational burdens in 27 types cancers, there was correlation between an increased burden and response to checkpoint inhibition PD-1 PD-L1.

Язык: Английский

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Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

New England Journal of Medicine, Год журнала: 2018, Номер 378(22), С. 2093 - 2104

Опубликована: Апрель 16, 2018

Nivolumab plus ipilimumab showed promising efficacy for the treatment of non–small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as potential biomarker benefit. In this part an open-label, multipart, 3 we examined progression-free survival with nivolumab versus chemotherapy among patients high (≥10 mutations per megabase).

Язык: Английский

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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

Cancer Discovery, Год журнала: 2018, Номер 8(9), С. 1069 - 1086

Опубликована: Авг. 16, 2018

Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community begin envision potentially curative therapeutic approaches. However, remarkable immunotherapies are currently limited a minority patients and indications, highlighting need for more effective novel Indeed, an extraordinary amount preclinical clinical investigation exploring potential negative positive costimulatory molecules. Insights into underlying biological mechanisms functions these molecules have, however, lagged significantly behind. Such understanding will be essential rational design next-generation immunotherapies. Here, we review current state our T-cell blockade, primarily CTLA4 PD-1, highlight conceptual gaps in knowledge.Significance: This provides overview immune therapy from basic biology immunologic perspective cancer research community. Cancer Discov; 8(9); 1069-86. ©2018 AACR.

Язык: Английский

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Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

Journal of Clinical Oncology, Год журнала: 2019, Номер 38(1), С. 1 - 10

Опубликована: Ноя. 4, 2019

Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands somatic mutations encode potential neoantigens. Such therefore likely be immunogenic, triggering upregulation immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study pembrolizumab patients with previously treated, advanced noncolorectal cancer.Eligible histologically/cytologically confirmed cancer who experienced failure prior therapy received 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, patient withdrawal. Radiologic imaging was performed 9 first year 12 thereafter. The primary end point objective response rate per Response Evaluation Criteria Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.Among 233 enrolled patients, 27 tumor types were represented, endometrial, gastric, cholangiocarcinoma, pancreatic cancers being most common. Median follow up 13.4 months. Objective 34.3% (95% CI, 28.3% 40.8%). progression-free survival 4.1 months 2.4 4.9 months) median overall 23.5 13.5 not reached). Treatment-related adverse events occurred 151 (64.8%). Thirty-four (14.6%) had grade 5 treatment-related events. Grade pneumonia one patient; there no other fatal events.Our demonstrates clinical benefit anti-programmed among treated unresectable metastatic Toxicity consistent previous experience monotherapy.

Язык: Английский

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Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

Annals of Oncology, Год журнала: 2018, Номер 30(1), С. 44 - 56

Опубликована: Ноя. 1, 2018

Treatment with immune checkpoint blockade (ICB) agents such as anti-programmed cell death protein 1 (PD-1), death-ligand (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated 4 (CTLA-4) can result in impressive response rates and durable disease remission but only a subset of patients cancer. Expression PD-L1 has demonstrated utility selecting for to ICB proven be an important biomarker patient selection. Tumor mutation burden (TMB) is emerging potential biomarker. However, refinement interpretation contextualization required.

Язык: Английский

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Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer

New England Journal of Medicine, Год журнала: 2020, Номер 383(23), С. 2207 - 2218

Опубликована: Дек. 2, 2020

Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 as compared with chemotherapy first-line therapy for MSI-H–dMMR advanced metastatic colorectal cancer is unknown.

Язык: Английский

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A view on drug resistance in cancer

Nature, Год журнала: 2019, Номер 575(7782), С. 299 - 309

Опубликована: Ноя. 13, 2019

Язык: Английский

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The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy

Nature reviews. Cancer, Год журнала: 2019, Номер 19(3), С. 133 - 150

Опубликована: Фев. 12, 2019

Язык: Английский

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