Integrative multi-omics analysis uncovers tumor-immune-gut axis influencing immunotherapy outcomes in ovarian cancer

Spencer R. Rosario, Mark D. Long, Shanmuga Chilakapati, Eduardo Cortes Gomez, Sebastiano Battaglia, Prashant K. Singh, Jianmin Wang, Katy Wang, Kristopher Attwood, Suzanne M. Hess, Robert McGray Aj, Kunle Odunsi, Brahm H. Segal, Gyorgy Paragh, Song Liu, Jennifer A. Wargo and Emese Zsiros ()
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Spencer R. Rosario: Roswell Park Comprehensive Cancer Center
Mark D. Long: Roswell Park Comprehensive Cancer Center
Shanmuga Chilakapati: Northeastern University
Eduardo Cortes Gomez: Roswell Park Comprehensive Cancer Center
Sebastiano Battaglia: Janssen Pharmaceuticals
Prashant K. Singh: Roswell Park Comprehensive Cancer Center
Jianmin Wang: Roswell Park Comprehensive Cancer Center
Katy Wang: Roswell Park Comprehensive Cancer Center
Kristopher Attwood: American College of Radiology
Suzanne M. Hess: Roswell Park Comprehensive Cancer Center
Robert McGray Aj: Roswell Park Comprehensive Cancer Center
Kunle Odunsi: University of Chicago Comprehensive Cancer Center
Brahm H. Segal: Roswell Park Comprehensive Cancer Center
Gyorgy Paragh: Roswell Park Comprehensive Cancer Center
Song Liu: Roswell Park Comprehensive Cancer Center
Jennifer A. Wargo: The University of Texas MD Anderson Cancer Center
Emese Zsiros: Roswell Park Comprehensive Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Recurrent ovarian cancer patients, especially those resistant to platinum, lack effective curative treatments. To address this, we conducted a phase 2 clinical trial (NCT02853318) combining pembrolizumab with bevacizumab, to increase T cell infiltration into the tumor, and oral cyclophosphamide, to reduce the number of regulatory T cells. The trial accrued 40 heavily pretreated recurrent ovarian cancer patients. The primary endpoint, progression free survival, was extended to a median of 10.2 months. The secondary endpoints demonstrated an objective response rate of 47.5%, and disease control in 30% of patients for over a year while maintaining a good quality of life. We performed comprehensive molecular, immune, microbiome, and metabolic profiling on samples of trial patients. Here, we show increased T and B cell clusters and distinct microbial patterns with amino acid and lipid metabolism are linked to exceptional clinical responses. This study suggests the immune milieu and host-microbiome can be leveraged to improve antitumor response in future immunotherapy trials.

Date: 2024
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DOI: 10.1038/s41467-024-54565-8

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