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Nivolumab plus ipilimumab induce hyper-progression in renal medullary carcinoma: results of a phase II trial and preclinical evidence

Author

Listed:
  • Melinda Soeung

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Xinmiao Yan

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Ciro Zanca

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Jing Qian

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas)

  • Menuka Karki

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas)

  • Fei Duan

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas)

  • Hania Khan

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology)

  • Li Zhang

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology)

  • David H. Peng

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Mariah Williams

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Rong He

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas)

  • Ziheng Chen

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Luigi Perelli

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, Department of Cancer Biology, The University of Texas)

  • Jianfeng Chen

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas)

  • Rebecca S. Tidwell

    (The University of Texas MD Anderson Cancer Center, Department of Biostatistics)

  • Pankaj K. Chauhan

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas)

  • Courtney N. Le

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology)

  • Truong N. A. Lam

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology)

  • Nirjar Bhattacharya

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Rutvi Shah

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS))

  • I-Lin Ho

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Jason P. Gay

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Caroline C. Carrillo

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Ningping Feng

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Kang Le

    (The University of Texas MD Anderson Cancer Center, Institute for Applied Cancer Science (IACS), Therapeutics Discovery Division)

  • Guang Gao

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Teresa L. Perry

    (The University of Texas MD Anderson Cancer Center, Institute for Applied Cancer Science (IACS), Therapeutics Discovery Division)

  • Faika Mseeh

    (The University of Texas MD Anderson Cancer Center, Institute for Applied Cancer Science (IACS), Therapeutics Discovery Division)

  • Yongying Jiang

    (The University of Texas MD Anderson Cancer Center, Institute for Applied Cancer Science (IACS), Therapeutics Discovery Division)

  • Quanyun A. Xu

    (The University of Texas MD Anderson Cancer Center, Institute for Applied Cancer Science (IACS), Therapeutics Discovery Division)

  • Niki Marie Zacharias

    (The University of Texas MD Anderson Cancer Center, Department of Urology)

  • Rahul A. Sheth

    (The University of Texas MD Anderson Cancer Center, Department of Interventional Radiology)

  • Tharakeswara K. Bathala

    (The University of Texas MD Anderson Cancer Center, Department of Diagnostic Imaging)

  • Priya Rao

    (The University of Texas MD Anderson Cancer Center, Department of Pathology)

  • Najat C. Daw

    (The University of Texas MD Anderson Cancer Center, Department of Pediatrics)

  • Durga N. Tripathi

    (Baylor college of Medicine, Center for Precision Environmental Health)

  • Cheryl L. Walker

    (Baylor college of Medicine, Center for Precision Environmental Health)

  • Mohammad M. Mohammad

    (The University of Texas MD Anderson Cancer Center, Institute for Personalized Cancer Therapy)

  • Jianhua Zhang

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Guangchun Han

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Yanshuo Chu

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Ruiping Wang

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Minghao Dang

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Enyu Dai

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Fuduan Peng

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Yunhe Liu

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Akshaya Jadhav

    (The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

  • Wenhua Lang

    (The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

  • Claudio A. Arrechedera

    (The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

  • Leticia Campos Clemente

    (The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

  • Edwin R. Parra

    (The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

  • Hsinyi Lu

    (The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

  • Cara L. Haymaker

    (The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

  • Ignacio I. Wistuba

    (The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

  • Andrew Futreal

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Andrea Viale

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine)

  • Michael J. Soth

    (The University of Texas MD Anderson Cancer Center, Institute for Applied Cancer Science (IACS), Therapeutics Discovery Division)

  • Philip Jones

    (The University of Texas MD Anderson Cancer Center, Institute for Applied Cancer Science (IACS), Therapeutics Discovery Division)

  • Joseph R. Marszalek

    (The University of Texas MD Anderson Cancer Center, Institute for Applied Cancer Science (IACS), Therapeutics Discovery Division)

  • Timothy Heffernan

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Giulio F. Draetta

    (The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION))

  • Nizar M. Tannir

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology)

  • Jianjun Gao

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas)

  • Linghua Wang

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS)
    The University of Texas MD Anderson Cancer Center, The James P. Allison Institute
    The University of Texas MD Anderson Cancer Center, Institute for Data Science in Oncology)

  • Giannicola Genovese

    (The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine
    The University of Texas MD Anderson Cancer Center, Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION)
    The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas)

  • Pavlos Msaouel

    (The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
    MD Anderson Cancer Center, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS)
    The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology)

Abstract

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here we report the results of a phase II clinical trial (NCT03274258) of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in patients with RMC, with objective response rate as primary outcome. Enrollment was halted for futility at a prespecified interim analysis as all 10 treated patients experienced rapid disease progression. 5/10 met radiological criteria for hyperprogression and median progression-free survival (secondary outcome) was 1.38 months (95% confidence interval: 1.28, 1.60). In a post-hoc single-cell RNA sequencing analysis, data from patients with RMC before and after nivolumab plus ipilimumab treatment indicated that immune checkpoint therapy (ICT) triggered an interferon-γ response that induced a “myeloid mimicry” program in tumor cells, regulated by the CEBPB / p300 axis and linked to proliferation and hyperprogression. In preclinical experiments using an immunocompetent somatic mosaic genetically engineered mouse model of RMC, combination ICT accelerated tumor growth while activating myeloid-affiliated transcriptional circuits. Selective pharmacologic inhibition of p300 suppressed this program and restored sensitivity to ICT. These findings reveal an adaptive mechanism of resistance to ICT in RMC and support targeting master myeloid regulators to enable therapeutic benefit.

Suggested Citation

  • Melinda Soeung & Xinmiao Yan & Ciro Zanca & Jing Qian & Menuka Karki & Fei Duan & Hania Khan & Li Zhang & David H. Peng & Mariah Williams & Rong He & Ziheng Chen & Luigi Perelli & Jianfeng Chen & Rebe, 2025. "Nivolumab plus ipilimumab induce hyper-progression in renal medullary carcinoma: results of a phase II trial and preclinical evidence," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65462-z
    DOI: 10.1038/s41467-025-65462-z
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