ArticleCancer cell2024
Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8
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Article in Cancer cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers, 2 of them syntheses that pooled it.
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84citing papers in PubMed, 2 pooled it
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
84 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Efficacy and safety of cadonilimab combined with chemotherapy for gastric or gastroesophageal junction adenocarcinoma: a single-arm meta-analysis.Frontiers in immunology · 2026Pooled it
- Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in the treatment of diffuse pleural mesothelioma: a systematic review and meta-analysis.Frontiers in immunology · 2025Pooled it
- Neoadjuvant PD1 plus CTLA-4 immune checkpoint blockade in surgically resectable recurrent glioblastoma: a randomized surgical window-of-opportunity trial.Nature communications · 2026Trial
- T-Cell Receptor and Immune Gene Expression Pharmacodynamics for Durvalumab Alone and with Tremelimumab or Bevacizumab in Unresectable Hepatocellular Carcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Article
- scXpand: Pan-cancer detection of T cell clonal expansion from single-cell RNA sequencing without paired single-cell TCR sequencing.Cell genomics · 2026Article
- T cell senescence and exhaustion: molecular mechanisms and immune rejuvenation for cancer immunotherapy.Signal transduction and targeted therapy · 2026Review
- Reprogramming Autophagy to Strengthen Antitumour Immunity: Advances in Immunotherapeutic Strategies.Immunology · 2026Review
- Review
- Translational insights and clinical challenges of targeting cancer stem cells.Signal transduction and targeted therapy · 2026Review
- Decoding T cell exhaustion in the tumour microenvironment.Experimental & molecular medicine · 2026Review
- γδ T cells show distinct responses to CMV after stem cell transplantation.Journal of molecular medicine (Berlin, Germany) · 2026Article
- HBO1 suppresses anti-tumor immunity of CD8⁺ T Cells in thyroid cancer by recruiting BRD4 to regulate VTCN1 expression.Cancer immunology, immunotherapy : CII · 2026Article
- Article
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Triple-Negative Breast Cancer: Molecular Subtypes; Immune Escape; Limitations of Current Immunotherapy; and the BTLA/HVEM/CD160 Axis as an Emerging Target.Current issues in molecular biology · 2026Review
- The evolving global landscape of first-in-class oncology drug innovation.Signal transduction and targeted therapy · 2026Review
- Acquired resistance of cancer therapies: Mechanisms and perspectives.Chinese medical journal · 2026Review
- Immune Checkpoint Inhibitors and Immunomodulators for Cancer Immunotherapy: Insights Into Resistance and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- The roles and heterogeneity of CD8International journal of molecular medicine · 2026Review
24 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
38 authors.
Kevin WangDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Paulina CoutifarisDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
David BrocksImmunai Inc, New York, NY 10016, USA.
Guanning WangDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Tarek AzarDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sabrina SolisDepartment of Medicine, Grossman School of Medicine, New York University, New York, NY 10016, USA.
Ajeya NandiDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Shaneaka AndersonDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nicholas HanDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sasikanth ManneDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Evgeny KinerImmunai Inc, New York, NY 10016, USA.
Chirag SacharImmunai Inc, New York, NY 10016, USA.
Minke LucasDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
Sangeeth GeorgeDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Patrick K YanDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Melanie W KierDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Amy I LaughlinDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Shawn KothariDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Josephine GilesDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Divij MathewDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Reem GhinnagowDepartment of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cecile AlanioInstitut Curie, PSL University, Inserm U932, Immunity and Cancer, 75005 Paris, France; Clinical Immunology and Immunomonitoring Laboratory, Institut Curie, Paris, France.
Ahron FlowersDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
Wei XuDepartment of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Daniel J TenneyBristol Myers Squibb, Princeton, NJ 08540, USA.
Xiaowei XuTara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ravi K AmaravadiDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Giorgos C KarakousisTara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lynn M SchuchterDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Marcus BuggertInstitute for Immunology and Immune Health, Philadelphia, PA 19104, USA.
Derek OldridgeDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Andy J MinnDepartment of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Philadelphia, PA 19104, USA.
Christian BlankDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden 2333 ZA, the Netherlands; Department of Hematology and Oncology, University Clinic of Regensburg (UKR), 93053 Regensburg, Germany.
Jeffrey S WeberDepartment of Medicine, Grossman School of Medicine, New York University, New York, NY 10016, USA.
Tara C MitchellDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Michael D FarwellAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ramin S HeratiDepartment of Medicine, Grossman School of Medicine, New York University, New York, NY 10016, USA. Electronic address: ramin.herati@nyulangone.org.
Alexander C HuangDivision of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: alexander.huang@pennmedicine.upenn.edu.
Funding
UNIVERSITY OF PENNSYLVANIA CAN CTR SUPPORT GRANTP30CA016520 · NCI · UNIVERSITY OF PENNSYLVANIA · PI SHELLEY L BERGER · 1985 to 2026
$222.3MVaccine FacilityP30CA016087 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI ADRIANA HEGUY · 1985 to 2026
$83.1MProject 4P50CA225450 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI OSMAN, IMAN, WEBER, JEFFREY S · 2019 to 2025
$12.5MTargeting exosomal PDL1 to improve immunotherapyP50CA261608 · NCI · WISTAR INSTITUTE · PI VILLANUEVA, JESSIE · 2021 to 2025
$11.3MTargeted Combination Therapy for MelanomaP50CA174523 · NCI · WISTAR INSTITUTE · PI HERLYN, MEENHARD F · 2014 to 2018
$11.1MGamma delta T cell based melanoma therapiesR01CA258113 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Meenhard F Herlyn, Xiaowei Xu · 2022 to 2026
$3.3MCorrelative biomarkers of IL-6 blockade combined with checkpoint inhibitionR01CA244936 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI MEHNERT, JANICE M. · 2020 to 2024
$2.9MRole of progenitor exhausted CD8 T cells and the progenitor niche in anti-PD1 efficacyR01CA273018 · NCI · UNIVERSITY OF PENNSYLVANIA · PI HUANG, ALEXANDER · 2022 to 2025
$2.6MRole of tumor burden in limiting durable reinvigoration by PD-1 blockadeK08CA230157 · NCI · UNIVERSITY OF PENNSYLVANIA · PI HUANG, ALEXANDER · 2019 to 2023
$1.0MNCI NIH HHS K08 CA230157NCI NIH HHS P30 CA016087NCI NIH HHS P30 CA016520NCI NIH HHS P50 CA174523NCI NIH HHS P50 CA225450NCI NIH HHS P50 CA261608NCI NIH HHS R01 CA244936NCI NIH HHS R01 CA258113NCI NIH HHS R01 CA273018
Abstract
Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8
Indexed as
CD8-Positive T-LymphocytesCTLA-4 AntigenImmune Checkpoint InhibitorsMelanomaProgrammed Cell Death 1 ReceptorAntineoplastic Combined Chemotherapy ProtocolsFemaleHumansMaleReceptors, Antigen, T-CellSingle-Cell AnalysisCTLA-4 AntigenCTLA4 protein, humanImmune Checkpoint InhibitorsPDCD1 protein, humanProgrammed Cell Death 1 ReceptorReceptors, Antigen, T-CellCheckpoint blockadeclonotypic analysiscombination checkpoint blockadeCTLA-4 blockadeimmunotherapymelanomaPD-1 blockadeprogenitor exhausted CD8(+) T cellssingle-cell sequencingT cell exhaustion
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.