Integrative multi-omics analysis uncovers tumor-immune-gut axis influencing immunotherapy outcomes in ovarian cancer
Spencer R. Rosario, Mark D. Long, Shanmuga Reddy Chilakapati, Eduardo Cortes Gomez, Sebastiano Battaglia, Prashant Singh, Jianmin Wang, Katy Wang, Kristopher Attwood, Suzanne M. Hess, AJ Robert McGray, Kunle Odunsi, Brahm H. Segal, György Paragh, Song Liu, Jennifer A. Wargo, Emese Zsíros
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.