Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells,Cancer Cell

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Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells
Cancer Cell ( IF 48.8 ) Pub Date : 2024-08-29 , DOI: 10.1016/j.ccell.2024.08.007
Kevin Wang ₁ , Paulina Coutifaris ₁ , David Brocks ₂ , Guanning Wang ₁ , Tarek Azar ₁ , Sabrina Solis ₃ , Ajeya Nandi ₁ , Shaneaka Anderson ₁ , Nicholas Han ₁ , Sasikanth Manne ₄ , Evgeny Kiner ₂ , Chirag Sachar ₂ , Minke Lucas ₅ , Sangeeth George ₁ , Patrick K Yan ₁ , Melanie W Kier ₁ , Amy I Laughlin ₁ , Shawn Kothari ₁ , Josephine Giles ₄ , Divij Mathew ₄ , Reem Ghinnagow ₆ , Cecile Alanio ₇ , Ahron Flowers ₈ , Wei Xu ₆ , Daniel J Tenney ₉ , Xiaowei Xu ₁₀ , Ravi K Amaravadi ₁₁ , Giorgos C Karakousis ₁₂ , Lynn M Schuchter ₁₁ , Marcus Buggert ₁₃ , Derek Oldridge ₁₄ , Andy J Minn ₁₅ , Christian Blank ₁₆ , Jeffrey S Weber ₃ , Tara C Mitchell ₁₁ , Michael D Farwell ₁₇ , Ramin S Herati ₃ , Alexander C Huang ₁₈

Affiliation

Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Immunai Inc, New York, NY 10016, USA.
Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10016, USA.
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institut Curie, PSL University, Inserm U932, Immunity and Cancer, 75005 Paris, France; Clinical Immunology and Immunomonitoring Laboratory, Institut Curie, Paris, France.
Division 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.
Bristol Myers Squibb, Princeton, NJ 08540, USA.
Tara 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.
Division 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.
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; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute for Immunology and Immune Health, Philadelphia, PA 19104, USA.
Department 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.
Department 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.
Department 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.
Abramson 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.
Division 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.

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+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

中文翻译：

抗 PD-1 和抗 CTLA-4 联合治疗可产生一波又一波的克隆反应，包括祖细胞耗竭的 CD8+ T 细胞

抗 PD-1 和抗 CTLA-4 抗体的联合检查点阻断在黑色素瘤中显示出有希望的疗效。然而，人类的潜在机制仍不清楚。在这里，我们对 36 名接受抗 PD-1、抗 CTLA-4 或联合治疗的 IV 期黑色素瘤患者进行了配对的单细胞 RNA 和 T 细胞受体（TCR）测序。我们开发了算法 Cyclone 来跟踪时间克隆动力学和潜在的细胞状态。检查点阻断诱导克隆性 T 细胞反应波，这些反应在不同时间点达到峰值。与单药治疗相比，联合治疗在 6 周和 9 周时导致更大程度的克隆反应，包括黑色素瘤特异性 CD8+ T 细胞和耗竭的 CD8+ T 细胞（TEX）克隆。TEX 的重点分析确定，抗 CTLA-4 诱导祖细胞 TEX 的强烈扩增和增殖，这与抗 PD-1 协同作用，在联合治疗期间重振 TEX。这些下一代免疫分析方法可以指导新型联合策略的药物选择、时间表和剂量。

更新日期：2024-08-29

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