A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma

Johannes F Fahrmann, Neeraj Y Saini, Chang Chia-Chi, Ehsan Irajizad, Paolo Strati, Ranjit Nair, Luis E Fayad, Sairah Ahmed, Hun Ju Lee, Swaminathan Iyer, Raphael Steiner, Jody Vykoukal, Ranran Wu, Jennifer B Dennison, Loretta Nastoupil, Preetesh Jain, Michael Wang, Michael Green, Jason Westin, Viktoria Blumenberg, Marco Davila, Richard Champlin, Elizabeth J Shpall, Partow Kebriaei, Christopher R Flowers, Michael Jain, Robert Jenq, Christoph K Stein-Thoeringer, Marion Subklewe, Sattva S Neelapu, Sam Hanash, Johannes F Fahrmann, Neeraj Y Saini, Chang Chia-Chi, Ehsan Irajizad, Paolo Strati, Ranjit Nair, Luis E Fayad, Sairah Ahmed, Hun Ju Lee, Swaminathan Iyer, Raphael Steiner, Jody Vykoukal, Ranran Wu, Jennifer B Dennison, Loretta Nastoupil, Preetesh Jain, Michael Wang, Michael Green, Jason Westin, Viktoria Blumenberg, Marco Davila, Richard Champlin, Elizabeth J Shpall, Partow Kebriaei, Christopher R Flowers, Michael Jain, Robert Jenq, Christoph K Stein-Thoeringer, Marion Subklewe, Sattva S Neelapu, Sam Hanash

Abstract

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL.

Keywords: CAR-T cell therapy; biomarker; large B cell lymphoma; liquid biopsy; metabolites; prognostic.

Conflict of interest statement

Declaration of interests An Invention Disclosure Report related to findings reported herein has been submitted to the University of Texas. M.S. has received industry research support from Amgen, Gilead, Miltenyi Biotec, Morphosys, Roche, and Seattle Genetics and has served as a consultant/advisor to Amgen, BMS, Celgene, Gilead, Pfizer, Novartis, and Roche. She sits on the advisory boards of Amgen, Celgene, Gilead, Janssen, Novartis, Pfizer, and Seattle Genetics and serves on the speakers' bureau at Amgen, Celgene, Gilead, Janssen, and Pfizer. N.Y.S. has intellectual property rights in the field of cellular immunotherapy and microbiome. S.S.N. received personal fees from Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Bluebird Bio, and Unum Therapeutics; research support from Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, and Acerta; royalties from Takeda Pharmaceuticals; and has intellectual property rights related to cell therapy. M.G. reports research funding from Sanofi, Kite/Gilead, Abbvie, and Allogene, honoraria from Tessa Therapeutics and Daiichi Sankyo, and stock ownership of KDAc Therapeutics. P.S. received research support from Astrazeneca-Acerta and from ALX Oncology and is a consultant for Roche-Genentech and Hutchinson MediPharma. S.S.N. has received personal fees from Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics, and Bluebird Bio; research support from Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, and Acerta; and patents, royalties, or other intellectual property from Takeda Pharmaceuticals.

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Association between circulating lysophospholipids and polyamines with progression-free survival and overall survival in patients with B cell lymphoma treated with CAR-T (A and B) Dot plots represent hazard ratios (HRs) (95% CI) per unit increase in log2 scale of detected polyamines and lysophospholipids for progression-free survival (PFS) and overall survival (OS) in the test set (A) and the validation set (B).
Figure 2
Figure 2
Circulating polyamine levels post CAR-T cell infusion in patients with r/r LBCL Linear mixed models with random intercept and slope were incorporated to calculate the association between polyamine levels following CAR-T infusion. Reported values (slope and intercepts) in the table are the average representation of all calculated coefficients for each patient. p values were calculated from 10,000 bootstraps of the delta value between responders and non-responders.
Figure 3
Figure 3
Predictive performance of the 6-marker metabolite panel (6MetP) for CAR-T cell response in the test and validation set (A and B) AUC curves are shown using the 6MetP scores for distinguishing patients who had who progressive disease or died within 6 months following CAR T cell treatment from those patients who had an ongoing complete response in the test set (A) and the validation set (B).
Figure 4
Figure 4
Association between 6MetP scores and PFS and OS in patients with B cell lymphoma treated with CAR-T (A) Kaplan-Meier survival curves illustrate the association between the 6MetP > or ≤ an optimal cutoff value for prognosticating PFS and OS in the test set. The cutoff was established using log rank statistics in the test set and represents the optimal cutoff value for prognosticating PFS. Mantel Cox log rank tests were used to compare differences in survival curves, and 2-sided p values are reported. (B) Kaplan-Meier survival curves illustrate the association between the 6MetP > or ≤ an optimal cutoff value established in the test set for prognosticating PFS and OS in the validation set. Mantel Cox log rank tests were used to compare differences in survival curves, and 1-sided p values are reported.
Figure 5
Figure 5
B cell lymphomas exhibit elevated mRNA expression of polyamine metabolizing enzymes and high spermidine synthase gene expression is prognostic for poor OS (A) Violin plots illustrating mRNA expression of polyamine-metabolizing enzymes (PMEs) in diffuse large B cell lymphoma and normal B lymphocytes in the Basso lymphoma dataset. Statistical significance was determined by 2-sided Wilcoxon rank sum test. ODC1, ornithine decarboxylase 1; AMD1, adenosylmethionine decarboxylase 1; SRM, spermidine synthase; SMS, spermine synthase; SAT1, spermidine/spermine N1-acetyltransferase 1. (B) Dot plots illustrating HRs (95% CI) per unit increase in mRNA expression of PMEs, and PFS in The Cancer Genome Atlas (TCGA)-diffuse large B cell lymphoma (DLBCL) transcriptomic dataset and overall survival in the Lenz and Shipp B cell lymphoma transcriptomic datasets. (C) Kaplan-Meier survival curves for association between mRNA expression of SRM > or ≤ an optimal change point value, and PFS in the TCGA-DLBCL dataset and overall survival in the Lenz and Shipp B cell lymphoma datasets, respectively. (D) Dot plots illustrate spearman ρ coefficients (95% CI) for association between mRNA expression of PMEs ODC1, SRM, and SMS with gene-based signatures of immune-cell infiltrates and immune-checkpoint-blockade-related genes in the TCGA-DLBCL and Ma DLBCL transcriptomic datasets. Gene-based signatures were according to Bindea et al. ODC1, ornithine decarboxylase 1; AMD1, adenosylmethionine decarboxylase 1; SRM, spermidine synthase; SMS, spermine synthase; SAT1, spermidine/spermine N1-acetyltransferase 1.

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