{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T19:53:32Z","timestamp":1781812412721,"version":"3.54.5"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T00:00:00Z","timestamp":1673827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Infusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R\/R relapsed\/refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R\/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of pre-lymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6\/IL-10\/GDF-15\/IL-15\/CXCL9\/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Multivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> lymphocytes (38.6<jats:bold>%<\/jats:bold> vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg\/dl vs 1.00 mg\/dl, OR=7.133 [95% CI: 1.796-28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8<jats:sup>+<\/jats:sup>CD45RA<jats:sup>+<\/jats:sup>CD57<jats:sup>+<\/jats:sup> senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14<jats:sup>+<\/jats:sup> and CD45<jats:sup>+<\/jats:sup> myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8<jats:sup>+<\/jats:sup> T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8<jats:sup>+<\/jats:sup> T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1058126","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T05:16:10Z","timestamp":1673846170000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity"],"prefix":"10.3389","volume":"13","author":[{"given":"Serena","family":"De Matteis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Dicataldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Casadei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Storci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Laprovitera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Arpinati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Maffini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Cortelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Guarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Vaglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Naddeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Sinigaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Zazzeroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serafina","family":"Guadagnuolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica","family":"Tomassini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore Nicola","family":"Bertuccio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Messelodi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Ferracin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Bonaf\u00e8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Luigi","family":"Zinzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bonifazi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.cytogfr.2017.04.003","article-title":"Dysfunctional T cell metabolism in the tumor microenvironment","volume":"35","author":"Beckermann","year":"2017","journal-title":"Cytokine Growth Factor Rev"},{"key":"B2","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41408-021-00459-7","article-title":"CAR-T cell therapy: Current limitations and potential strategies","volume":"11","author":"Sterner","year":"2021","journal-title":"Blood Cancer J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1056\/NEJMoa1804980","article-title":"Tisagenlecleucel in adult relapsed or refractory diffuse Large b-cell lymphoma. t; JULIET investigators","volume":"380","author":"Schuster","year":"2019","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020004038","article-title":"Absolute lymphocyte count proliferation kinetics after CAR T-cell infusion impact response and relapse","volume":"5","author":"Faude","year":"2021","journal-title":"Blood Adv"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.577027","article-title":"Cytokines in CAR T cell-associated neurotoxicity","volume":"11","author":"Gust","year":"2020","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.758","article-title":"ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells","volume":"25","author":"Lee","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-021-10766-5","article-title":"Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity","volume":"269","author":"Pensato","year":"2022","journal-title":"J Neurol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1002\/ana.25502","article-title":"Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy","volume":"86","author":"Gust","year":"2019","journal-title":"Ann Neurol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nly064","article-title":"Neuropathology of a case with fatal CAR T-cell-associated cerebral edema","volume":"77","author":"Torre","year":"2018","journal-title":"J Neuropathol Exp Neurol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.36.5_suppl.122","article-title":"Correlation of patient characteristics and biomarkers with clinical outcomes of JCAR017 in R\/R aggressive b-NHL (TRANSCEND NHL 001 study)","volume":"36","author":"Siddiqi","year":"2018","journal-title":"J Clin Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.02103","article-title":"Axicabtagene ciloleucel in the non-trial setting: Outcomes and correlates of response, resistance, and toxicity","volume":"38","author":"Jacobson","year":"2020","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002394","article-title":"Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large b-cell lymphoma","volume":"4","author":"Locke","year":"2020","journal-title":"Blood Adv"},{"key":"B13","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1182\/blood-2018-10-881722","article-title":"GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts","volume":"133","author":"Sterner","year":"2019","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0036-4","article-title":"Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells","volume":"24","author":"Norelli","year":"2018","journal-title":"Nat Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0041-7","article-title":"CAR T cell\u2013induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade","volume":"24","author":"Giavridis","year":"2018","journal-title":"Nat Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0698","article-title":"Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells","volume":"7","author":"Gust","year":"2017","journal-title":"Canc Discovery"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01916-x","article-title":"Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large b cell lymphoma","volume":"28","author":"Scholler","year":"2022","journal-title":"J Nat Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1061-7","article-title":"Characteristics of anti-CD19 CAR T-cell infusion products associated with efficacy and toxicity in patients with large b-cell lymphomas","volume":"26","author":"Deng","year":"2020","journal-title":"Nat Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51355","article-title":"Comparison of SimoaTM and EllaTM to assess serum neurofilament-light chain in multiple sclerosis","volume":"8","author":"Gauthier","year":"2021","journal-title":"Ann Clin Transl Neurol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfac259","article-title":"Identification of a serum and urine extracellular vesicle signature predicting renal outcome after kidney transplant","author":"Burrello","year":"2022","journal-title":"Nephrol Dial Transplant"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00415-022-11373-8","article-title":"Association of admission serum levels of neurofilament light chain and in-hospital mortality in geriatric patients with COVID-19","volume":"16","author":"Marchegiani","year":"2022","journal-title":"J Neurol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004575","article-title":"CRP and ferritin in addition to the EASIX score predict CAR-T\u2013related toxicity","volume":"5","author":"Greenbaum","year":"2021","journal-title":"Blood Adv"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1319","article-title":"Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with b-cell acute lymphoblastic leukemia","volume":"8","author":"Santomasso","year":"2018","journal-title":"Cancer Discovery"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020010543","article-title":"CAR-HEMATOTOX: a model for CAR t-cell\u2013related hematologic toxicity in relapsed\/refractory large b-cell lymphoma","volume":"138","author":"Rejeski","year":"2021","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nrclinonc.2017.148","article-title":"Chimeric antigen receptor T-cell therapy - assessment and management of toxicities","volume":"15","author":"Neelapu","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290","article-title":"Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia","volume":"6","author":"Teachey","year":"2016","journal-title":"Cancer Discovery"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-793141","article-title":"Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy","volume":"30","author":"Hay","year":"2017","journal-title":"Blood"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.877477","article-title":"EASIX and severe endothelial complications after CD19-directed CAR-T cell therapy-a cohort study","volume":"13","author":"Korell","year":"2022","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jim.2016.03.005","article-title":"Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and\/or siltuximab following CAR T cell therapy","volume":"34","author":"Chen","year":"2016","journal-title":"J Immunol Methods"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.35.15suppl.7024","article-title":"Baseline and early post-treatment clinical and laboratory factors associated with severe neurotoxicity following 19-28z CAR T cells in adult patients with relapsed b-ALL","volume":"35","author":"Park","year":"2017","journal-title":"J Clin Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201100104","article-title":"Inflamm-aging of the stem cell niche: breast cancer as a paradigmatic example: breakdown of the multi-shell cytokine network fuels cancer in aged people","volume":"34","author":"Bonaf\u00e8","year":"2012","journal-title":"Bioessays"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2020.104254","article-title":"IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy","volume":"359","author":"Weber","year":"2021","journal-title":"Cell Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000599","article-title":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","volume":"18","author":"Basisty","year":"2020","journal-title":"PloS Biol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1038\/s43587-021-00082-y","article-title":"An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging","volume":"1","author":"Sayed","year":"2021","journal-title":"Nat Aging"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021006144","article-title":"Neurofilament light chain serum levels correlate with the severity of neurotoxicity after CAR T-cell treatment","volume":"6","author":"Schoeberl","year":"2022","journal-title":"Blood Adv"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1058126\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T05:16:14Z","timestamp":1673846174000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1058126\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,16]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2022.1058126"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1058126","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,16]]},"article-number":"1058126"}}