Treatment of muscle‐invasive and advanced bladder cancer in 2020

CA A Cancer Journal for Clinicians, Journal Year: 2020, Volume and Issue: 70(5), P. 404 - 423

Published: Aug. 7, 2020

Abstract Bladder cancer accounts for nearly 170,000 deaths worldwide annually. For over 4 decades, the systemic management of muscle‐invasive and advanced bladder has primarily consisted platinum‐based chemotherapy. Over past 10 years, innovations in sequencing technologies have led to rapid genomic characterization cancer, deepening our understanding pathogenesis exposing potential therapeutic vulnerabilities. On basis its high mutational burden, immune checkpoint inhibitors were investigated revealing durable responses a subset patients. These agents are now approved several indications highlight changing treatment landscape cancer. In addition, commonly expressed molecular targets leveraged develop targeted therapies, such as fibroblast growth factor receptor antibody‐drug conjugates. The development novel therapies also stimulated investigations into optimizing approaches Herein, authors review history management, important characteristics describe major advances treatment, offer future directions development.

Language: Английский

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Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%

Journal of Clinical Oncology, Journal Year: 2021, Volume and Issue: 39(21), P. 2339 - 2349

Published: April 19, 2021

We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled pembrolizumab compared with platinum-based chemotherapy in patients previously untreated NSCLC a programmed death ligand-1 (PD-L1) tumor proportion score at least 50% and no sensitizing

Language: Английский

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Targeting STAT3 in Cancer Immunotherapy

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Sept. 24, 2020

Abstract As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 broadly hyperactivated both cancer non-cancerous cells within tumor ecosystem plays important roles inhibiting expression crucial activation regulators promoting production immunosuppressive factors. Therefore, targeting pathway has emerged as promising therapeutic strategy cancers. In this review, we outline importance tumorigenesis its regulation, highlight current status development STAT3-targeting approaches. We also summarize discuss recent advances STAT3-based combination immunotherapy detail. These endeavors provide new insights into translational application may contribute to promotion more effective treatments toward malignancies.

Language: Английский

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Toward personalized treatment approaches for non-small-cell lung cancer

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(8), P. 1345 - 1356

Published: Aug. 1, 2021

Language: Английский

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Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer

Cancer Discovery, Journal Year: 2020, Volume and Issue: 10(9), P. 1330 - 1351

Published: May 20, 2020

A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single from cancer. We validate the five most abundant flow cytometry silico analyses other cancer types, highlighting their relevance. Myofibroblasts 0 3, characterized extracellular matrix proteins TGFβ signaling, respectively, are indicative primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 CTLA4 protein levels regulatory T lymphocytes (Tregs), which, turn, increases cluster 3/TGFβ-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific Tregs uncovers role resistance. SIGNIFICANCE: Our work provides significant advance characterizing understanding FAP+ CAF reached high resolution at single-cell level, which enabled us associated with Identification cluster-specific signatures paves way for therapeutic options combination immunotherapies.This article is highlighted In This Issue feature, p. 1241.

Language: Английский

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First-Line Immunotherapy for Non–Small-Cell Lung Cancer

Journal of Clinical Oncology, Journal Year: 2022, Volume and Issue: 40(6), P. 586 - 597

Published: Jan. 5, 2022

For patients with metastatic non-small-cell lung cancer (mNSCLC), the last decade has been characterized by critical progress that contributed to substantially improved survival. In particular, development of specific antibodies against programmed death (PD-1) receptor, death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 receptor in therapeutic strategy mNSCLC either first- or second-line settings have led unprecedented prolonged survival for a proportion these patients. Although clinical immune checkpoint inhibitors anti-PD-1 PD-L1 therapies largely began as monotherapy setting, more recent shifted toward combination approaches first-line well integration immunotherapy into paradigm earlier stages. Today, exception harboring targetable oncogenes, nearly all receive PD-1 therapy settings. Here we report current status together challenges selecting best immunotherapeutic approach individual patient.

Language: Английский

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The Next Decade of Immune Checkpoint Therapy

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(4), P. 838 - 857

Published: April 1, 2021

Immune checkpoint therapy (ICT) can provide durable clinical responses and improve overall survival. However, only subsets of patients with specific tumor types respond to ICT. Thus, significant challenges remain, including understanding pathways resistance, optimizing patient selection, improving management immune-related adverse events, identifying rational therapeutic combinations. These will need a focused approach encompassing both basic research, the integration reverse translational studies. This integrated lead identification potential targets for subsequent trials, which guide decisions as we develop novel combination strategies maximize efficacy minimize toxicities patients. SIGNIFICANCE: ICTs induce antitumor cancer. Recent evidence suggests that combinatorial response by overcoming primary adaptive resistance mechanisms, although these may carry an increased risk immune-mediated toxicities. review surveys current mechanisms active areas investigation, proposes path forward minimizing through better selection

Language: Английский

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Lung cancer immunotherapy: progress, pitfalls, and promises

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Feb. 21, 2023

Abstract Lung cancer is the primary cause of mortality in United States and around globe. Therapeutic options for lung treatment include surgery, radiation therapy, chemotherapy, targeted drug therapy. Medical management often associated with development resistance leading to relapse. Immunotherapy profoundly altering approach owing its tolerable safety profile, sustained therapeutic response due immunological memory generation, effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground cancer. Recent advances adoptive cell therapy (CAR T, TCR, TIL), clinical trials on cancer, hurdles discussed this review. patients (without targetable oncogenic driver alteration) reveal significant responses when treated programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that loss effective anti-tumor immunity tumor evolution. vaccines combined immune inhibitors (ICI) can achieve better effects. To end, present article encompasses detailed overview recent developments immunotherapeutic landscape targeting small (SCLC) non-small (NSCLC). Additionally, review also explores implication nanomedicine immunotherapy as well combinatorial application traditional along regimens. Finally, ongoing trials, obstacles, future outlook strategy highlighted boost further research field.

Language: Английский

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Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non–Small Cell Lung Cancer

JAMA Oncology, Journal Year: 2020, Volume and Issue: 6(5), P. 661 - 661

Published: April 9, 2020

Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity patients metastatic non-small lung cancer.To compare durvalumab, without tremelimumab, chemotherapy a first-line treatment for cancer.This open-label, phase 3 randomized trial (MYSTIC) was conducted at 203 cancer centers 17 countries. Patients treatment-naive, who had no sensitizing EGFR ALK genetic alterations were to receive durvalumab plus chemotherapy. Data collected from July 21, 2015, October 30, 2018.Patients (1:1:1) (20 mg/kg every weeks), weeks) tremelimumab (1 weeks, up doses), platinum-based doublet chemotherapy.The primary end points, assessed ≥25% of tumor cells expressing PD-L1, overall survival (OS) vs chemotherapy, and OS progression-free (PFS) Analysis blood mutational burden (bTMB) exploratory.Between June 8, 2016, 1118 randomized. Baseline demographic disease characteristics balanced between groups. Among 488 median 16.3 months (95% CI, 12.2-20.8) 12.9 10.5-15.0) (hazard ratio [HR], 0.76; 97.54% 0.56-1.02; P = .04 [nonsignificant]). Median 11.9 9.0-17.7) (HR 0.85; 98.77% 0.61-1.17; .20). PFS 3.9 2.8-5.0) 5.4 4.6-5.8) (HR, 1.05; 99.5% 0.72-1.53; .71). 809 evaluable bTMB, those bTMB ≥20 mutations per megabase showed improved (median OS, 21.9 [95% 11.4-32.8] 10.0 8.1-11.7]; HR, 0.49; 95% 0.32-0.74). Treatment-related adverse events grade higher occurred 55 (14.9%) 369 received 85 (22.9%) 371 119 (33.8%) 352 These led 2 (0.5%), 6 (1.6%), (0.9%) patients, respectively.The MYSTIC study did not meet points PD-L1. Exploratory analyses identified threshold optimal benefit tremelimumab.ClinicalT rials.gov Identifier: NCT02453282.

Language: Английский

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Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial

The Lancet Oncology, Journal Year: 2020, Volume and Issue: 22(1), P. 51 - 65

Published: Dec. 5, 2020

Language: Английский

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