An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma

Sandeep S. Raj; Teng Fei; Shalev Fried; Andrew Ip; Joshua A. Fein; Lori A. Leslie; Ana Alarcon Tomas; Doris Leithner; Jonathan U. Peled; Magdalena Corona; Parastoo B. Dahi; Ivetta Danylesko; Zachary Epstein-Peterson; Tyler Funnell; Sergio A. Giralt; Elad Jacoby; Meirav Kedmi; Ivan Landego; Richard J. Lin; Allison Parascondola; Lauren 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

doi:10.1038/s41591-025-03532-x

An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma

Sandeep S. Raj, Teng Fei, Shalev Fried, Andrew Ip, Joshua A. Fein, Lori A. Leslie, Ana Alarcon Tomas, Doris Leithner, Jonathan U. Peled, Magdalena Corona, Parastoo B. Dahi, Ivetta Danylesko, Zachary Epstein-Peterson, Tyler Funnell, Sergio A. Giralt, Elad Jacoby, Meirav Kedmi, Ivan Landego, Richard J. Lin, Allison ParascondolaLauren 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	53
Journal	Nature Medicine
DOIs	https://doi.org/10.1038/s41591-025-03532-x
State	Accepted/In press - 2025

Funding

Funders	Funder number
Parker Institute for Cancer Immunotherapy
Long Island Sound Chapter
Cycle for Survival
Fundación Alfonso Martín Escudero
National Institutes of Health
Starr Cancer Consortium
Susan and Peter Solomon Family Fund
American Society for Transplantation and Cellular Therapy
Seres Therapeutics
Lymphoma Foundation
NHLBI NIH	K08HL143189
National Heart, Lung, and Blood Institute	R01-HL123340, R01-HL147584
Memorial Sloan-Kettering Cancer Center	P30 CA008748
Swim Across America	R01-CA228308, R01-CA228358
Clinical and Translational Science Center, Weill Cornell Medicine	2UL1-TR-2384
NIH-NCI	K08CA282987
National Institute on Aging	P01-AG052359
National Cancer Institute	P01-CA023766

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41591-025-03532-x

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Raj, S. S., Fei, T., Fried, S., Ip, A., Fein, J. A., Leslie, L. A., Alarcon Tomas, A., Leithner, D., Peled, J. U., Corona, M., Dahi, P. B., Danylesko, I., Epstein-Peterson, Z., Funnell, T., Giralt, S. A., Jacoby, E., Kedmi, M., Landego, I., Lin, R. J., ... Shouval, R. (Accepted/In press). An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma. Nature Medicine, Article 53. https://doi.org/10.1038/s41591-025-03532-x

@article{47895fb103194771b044ea06f5261c6f,

title = "An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma",

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.",

author = "Raj, {Sandeep S.} and Teng Fei and Shalev Fried and Andrew Ip and Fein, {Joshua A.} and Leslie, {Lori A.} and {Alarcon Tomas}, Ana and Doris Leithner and Peled, {Jonathan U.} and Magdalena Corona and Dahi, {Parastoo B.} and Ivetta Danylesko and Zachary Epstein-Peterson and Tyler Funnell and Giralt, {Sergio A.} and Elad Jacoby and Meirav Kedmi and Ivan Landego and Lin, {Richard J.} and Allison Parascondola and Lauren Pascual and Natali Orozco and Park, {Jae H.} and Palomba, {M. Lia} and Gilles Salles and Amethyst Saldia and Heiko Sch{\"o}der and Inbal Sdayoor and Shah, {Gunjan L.} and Michael Scordo and Noga Shem-Tov and Avichai Shimoni and John Slingerland and Ronit Yerushalmi and Arnon Nagler and Greenbaum, {Benjamin D.} and Vickers, {Andrew J.} and Suh, {Hyung C.} and Abraham Avigdor and Perales, {Miguel Angel} and {van den Brink}, {Marcel R.M.} and Roni Shouval",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1038/s41591-025-03532-x",

language = "אנגלית",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

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Raj, SS, Fei, T, Fried, S, Ip, A, Fein, JA, Leslie, LA, Alarcon Tomas, A, Leithner, D, Peled, JU, Corona, M, Dahi, PB, Danylesko, I, Epstein-Peterson, Z, Funnell, T, Giralt, SA, Jacoby, E , Kedmi, M, Landego, I, Lin, RJ, Parascondola, A, Pascual, L, Orozco, N, Park, JH, Palomba, ML, Salles, G, Saldia, A, Schöder, H, Sdayoor, I, Shah, GL, Scordo, M, Shem-Tov, N, Shimoni, A, Slingerland, J, Yerushalmi, R, Nagler, A, Greenbaum, BD, Vickers, AJ, Suh, HC, Avigdor, A, Perales, MA, van den Brink, MRM & Shouval, R 2025, 'An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma', Nature Medicine. https://doi.org/10.1038/s41591-025-03532-x

TY - JOUR

T1 - An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma

AU - Raj, Sandeep S.

AU - Fei, Teng

AU - Fried, Shalev

AU - Ip, Andrew

AU - Fein, Joshua A.

AU - Leslie, Lori A.

AU - Alarcon Tomas, Ana

AU - Leithner, Doris

AU - Peled, Jonathan U.

AU - Corona, Magdalena

AU - Dahi, Parastoo B.

AU - Danylesko, Ivetta

AU - Epstein-Peterson, Zachary

AU - Funnell, Tyler

AU - Giralt, Sergio A.

AU - Jacoby, Elad

AU - Kedmi, Meirav

AU - Landego, Ivan

AU - Lin, Richard J.

AU - Parascondola, Allison

AU - Pascual, Lauren

AU - Orozco, Natali

AU - Park, Jae H.

AU - Palomba, M. Lia

AU - Salles, Gilles

AU - Saldia, Amethyst

AU - Schöder, Heiko

AU - Sdayoor, Inbal

AU - Shah, Gunjan L.

AU - Scordo, Michael

AU - Shem-Tov, Noga

AU - Shimoni, Avichai

AU - Slingerland, John

AU - Yerushalmi, Ronit

AU - Nagler, Arnon

AU - Greenbaum, Benjamin D.

AU - Vickers, Andrew J.

AU - Suh, Hyung C.

AU - Avigdor, Abraham

AU - Perales, Miguel Angel

AU - van den Brink, Marcel R.M.

AU - Shouval, Roni

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

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M1 - 53

ER -

An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma

Abstract

Funding

UN SDGs

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