Nivolumab plus ipilimumab induce hyper-progression in renal medullary carcinoma: results of a phase II trial and preclinical evidence
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.
Article Details
Authors (66)
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
Department of Interventional Radiology The University of Texas MD Anderson Cancer Center Houston Texas USA
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
Pavlos Msaouel