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

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.

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Journal
Nature Communications
Published
2025-11-25
DOI
https://doi.org/10.1038/s41467-025-65462-z
Citations
2
Primary Topic
Renal cell carcinoma treatment
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article
Field-Weighted Citation Impact
3.04

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

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

Melinda Soeung, Akshaya Jadhav, Mariah Williams, Hsin‐Yi Lu, Rahul A. Sheth, Mohammad M. Mohammad, Menuka Karki, Yongying Jiang, Niki Marie Zacharias, Rebecca S. Tidwell, Ignacio I. Wistuba, Truong Lam, Fuduan Peng, Luigi Perelli, Giulio Draetta, Guangchun Han, Edwin R. Parra, Caroline C. Carrillo, Rutvi Shah, Guang R. Gao, Giannicola Genovese, David H. Peng, Joseph R. Marszalek, Ziheng Chen, Cara Haymaker, Linghua Wang, Ciro Zanca, Priya Rao, Nizar M. Tannir, Jing Qian, Cheryl L. Walker, I-Lin Ho, Timothy P. Heffernan, P. Andrew Futreal, Philip Jones, Minghao Dang, Courtney N. Le, Michael Soth, Fei Duan, Jianjun Gao, Nirjar Bhattacharya, Ningping Feng, Xinmiao Yan, Andrea Viale, Durga Nand Tripathi, Letícia Campos Clemente, Rong Lucy He, Pavlos Msaouel, Tharakeswara Bathala, Faika Mseeh, Yanshuo Chu, Hania Khan, Teresa Perry, Najat C. Daw, Claudio A. Arrechedera, Jianfeng Chen, Li Zhang, Jianhua Zhang, Yunhe Liu, Enyu Dai, Kang Le, Pankaj Kumar Chauhan, Ruiping Wang, Jason Gay, Quanyun A. Xu, Wenhua Lang
article en
2 citations

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.

Nature CommunicationsVol. 16(1)
The University of Texas MD Anderson Cancer Center (US), Baylor College of Medicine (US), The University of Texas Health Science Center at Houston (US)
U.S. Department of Defense, Gateway for Cancer Research, Bristol-Myers Squibb, Andrew Sabin Family Foundation, Mark Foundation For Cancer Research, University of Texas MD Anderson Cancer Center, National Cancer Institute, Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Moonshot Research and Development Program
Openalex Percentile: Top 7%
Renal cell carcinoma treatment
3.04
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