An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma
Sandeep Raj, Teng Fei, Shalev Fried, Andrew Ip, Joshua Fein, Lori A. Leslie, Ana Alarcón Tomás, Doris Leithner, Jonathan U. Peled, Magdalena Corona, Parastoo B. Dahi, Ivetta Danylesko, Zachary D. Epstein‐Peterson, Tyler Funnell, Sergio Giralt, Elad Jacoby, Meirav Kedmi, Ivan Landego, Richard J. Lin, Allison Parascondola, L.C. Fernando Pascual, Natali Orozco, Jae H. Park, M. Lia Palomba, Gilles Salles, Amethyst Saldia, Heiko Schöder, Inbal Sdayoor, Gunjan L. Shah, Michael Scordo, Noga Shem‐Tov, Avichai Shimoni, John Slingerland, Ronit Yerushalmi, Arnon Nagler, Benjamin D. Greenbaum, Andrew J. Vickers, Hyung C. Suh, Abraham Avigdor, Miguel‐Angel Perales, Marcel R.M. van den Brink, Roni Shouval
Abstract
Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60–4.91; P < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy. A preinfusion circulatory inflammation biomarker-based signature predicts the likelihood of treatment failure in patients with non-Hodgkin lymphoma who were treated with CAR-T cell therapy, with an inflammatory cluster assignment being prognostic of clinical response and survival outcomes.