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

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, Rebecca S. Tidwell, Pankaj K. Chauhan, Courtney N. Le, Truong N. A. Lam, Nirjar Bhattacharya, Rutvi Shah, I-Lin Ho, Jason P. Gay, Caroline C. Carrillo, Ningping Feng, Kang Le, Guang Gao, Teresa L. Perry, Faika Mseeh, Yongying Jiang, Quanyun A. Xu, Niki Marie Zacharias, Rahul A. Sheth, Tharakeswara K. Bathala, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Mohammad M. Mohammad, Jianhua Zhang, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Edwin R. Parra, Hsinyi Lu, Cara L. Haymaker, Ignacio I. Wistuba, Andrew Futreal, Andrea Viale, Michael J. Soth, Philip Jones, Joseph R. Marszalek, Timothy Heffernan, Giulio F. Draetta, Nizar M. Tannir, Jianjun Gao (), Linghua Wang (), Giannicola Genovese () and Pavlos Msaouel ()
Additional contact information
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
Menuka Karki: The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
Fei Duan: The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
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
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
Jianfeng Chen: The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology
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
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
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
Linghua Wang: The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine
Giannicola Genovese: The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine
Pavlos Msaouel: The University of Texas MD Anderson Cancer Center, Department of Genitourinary Medical Oncology

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65462-z

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