CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells
BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific...
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| Veröffentlicht in: | The Journal of clinical investigation 2024-07, Vol.134 (14), p.1-16 |
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| creator | Storci, Gianluca De Felice, Francesco Ricci, Francesca Santi, Spartaco Messelodi, Daria Bertuccio, Salvatore Nicola Laprovitera, Noemi Dicataldo, Michele Rossini, Lucrezia De Matteis, Serena Casadei, Beatrice Vaglio, Francesca Ursi, Margherita Barbato, Francesco Roberto, Marcello Guarino, Maria Asioli, Gian Maria Arpinati, Mario Cortelli, Pietro Maffini, Enrico Tomassini, Enrica Tassoni, Marta Cavallo, Carola Iannotta, Francesco Naddeo, Maria Tazzari, Pier Luigi Dan, Elisa Pellegrini, Cinzia Guadagnuolo, Serafina Carella, Matteo Sinigaglia, Barbara Pirazzini, Chiara Severi, Caterina Garagnani, Paolo Kwiatkowska, Katarzyna Malgorzata Ferracin, Manuela Zinzani, Pier Luigi Bonafè, Massimiliano Bonifazi, Francesca |
| description | BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/μL at hour +1 or greater than 224.5 CAR+EVs/μL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring). |
| doi_str_mv | 10.1172/JCI173096 |
| format | Article |
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This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/μL at hour +1 or greater than 224.5 CAR+EVs/μL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).</description><identifier>ISSN: 1558-8238</identifier><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI173096</identifier><identifier>PMID: 38833312</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adult ; Aged ; Antigen-presenting cells ; Antigens, CD19 - immunology ; B-cell lymphoma ; Biomarkers ; CD19 antigen ; Cell activation ; Convulsions & seizures ; Ecosystem recovery ; Edema ; Effector cells ; Extracellular vesicles ; Extracellular Vesicles - immunology ; Extracellular Vesicles - metabolism ; Female ; Humans ; Immunotherapy, Adoptive ; Lymphocytes ; Lymphocytes T ; Lymphoma ; Lymphoma, B-Cell - blood ; Lymphoma, B-Cell - immunology ; Lymphoma, B-Cell - therapy ; Male ; Middle Aged ; Nanoparticles ; Neurotoxicity ; Pathogenesis ; Patients ; Plasma ; Pluripotency ; Prospective Studies ; Receptors, Chimeric Antigen - immunology ; Stem cells</subject><ispartof>The Journal of clinical investigation, 2024-07, Vol.134 (14), p.1-16</ispartof><rights>Copyright American Society for Clinical Investigation Jul 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c308t-2bdb83940bd6bbf3cc3a63f6a454ac1f93975cf1865cc1e0cc9c9b9bb070eafa3</cites><orcidid>0000-0002-1536-5024 ; 0000-0001-9856-7053</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38833312$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Storci, Gianluca</creatorcontrib><creatorcontrib>De Felice, Francesco</creatorcontrib><creatorcontrib>Ricci, Francesca</creatorcontrib><creatorcontrib>Santi, Spartaco</creatorcontrib><creatorcontrib>Messelodi, Daria</creatorcontrib><creatorcontrib>Bertuccio, Salvatore Nicola</creatorcontrib><creatorcontrib>Laprovitera, Noemi</creatorcontrib><creatorcontrib>Dicataldo, Michele</creatorcontrib><creatorcontrib>Rossini, Lucrezia</creatorcontrib><creatorcontrib>De Matteis, Serena</creatorcontrib><creatorcontrib>Casadei, Beatrice</creatorcontrib><creatorcontrib>Vaglio, Francesca</creatorcontrib><creatorcontrib>Ursi, Margherita</creatorcontrib><creatorcontrib>Barbato, Francesco</creatorcontrib><creatorcontrib>Roberto, Marcello</creatorcontrib><creatorcontrib>Guarino, Maria</creatorcontrib><creatorcontrib>Asioli, Gian Maria</creatorcontrib><creatorcontrib>Arpinati, Mario</creatorcontrib><creatorcontrib>Cortelli, Pietro</creatorcontrib><creatorcontrib>Maffini, Enrico</creatorcontrib><creatorcontrib>Tomassini, Enrica</creatorcontrib><creatorcontrib>Tassoni, Marta</creatorcontrib><creatorcontrib>Cavallo, Carola</creatorcontrib><creatorcontrib>Iannotta, Francesco</creatorcontrib><creatorcontrib>Naddeo, Maria</creatorcontrib><creatorcontrib>Tazzari, Pier Luigi</creatorcontrib><creatorcontrib>Dan, Elisa</creatorcontrib><creatorcontrib>Pellegrini, Cinzia</creatorcontrib><creatorcontrib>Guadagnuolo, Serafina</creatorcontrib><creatorcontrib>Carella, Matteo</creatorcontrib><creatorcontrib>Sinigaglia, Barbara</creatorcontrib><creatorcontrib>Pirazzini, Chiara</creatorcontrib><creatorcontrib>Severi, Caterina</creatorcontrib><creatorcontrib>Garagnani, Paolo</creatorcontrib><creatorcontrib>Kwiatkowska, Katarzyna Malgorzata</creatorcontrib><creatorcontrib>Ferracin, Manuela</creatorcontrib><creatorcontrib>Zinzani, Pier Luigi</creatorcontrib><creatorcontrib>Bonafè, Massimiliano</creatorcontrib><creatorcontrib>Bonifazi, Francesca</creatorcontrib><title>CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/μL at hour +1 or greater than 224.5 CAR+EVs/μL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).</description><subject>Adult</subject><subject>Aged</subject><subject>Antigen-presenting cells</subject><subject>Antigens, CD19 - immunology</subject><subject>B-cell lymphoma</subject><subject>Biomarkers</subject><subject>CD19 antigen</subject><subject>Cell activation</subject><subject>Convulsions & seizures</subject><subject>Ecosystem recovery</subject><subject>Edema</subject><subject>Effector cells</subject><subject>Extracellular vesicles</subject><subject>Extracellular Vesicles - immunology</subject><subject>Extracellular Vesicles - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Immunotherapy, Adoptive</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Lymphoma</subject><subject>Lymphoma, B-Cell - blood</subject><subject>Lymphoma, B-Cell - immunology</subject><subject>Lymphoma, B-Cell - therapy</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Nanoparticles</subject><subject>Neurotoxicity</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Plasma</subject><subject>Pluripotency</subject><subject>Prospective Studies</subject><subject>Receptors, Chimeric Antigen - immunology</subject><subject>Stem 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extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells</title><author>Storci, Gianluca ; De Felice, Francesco ; Ricci, Francesca ; Santi, Spartaco ; Messelodi, Daria ; Bertuccio, Salvatore Nicola ; Laprovitera, Noemi ; Dicataldo, Michele ; Rossini, Lucrezia ; De Matteis, Serena ; Casadei, Beatrice ; Vaglio, Francesca ; Ursi, Margherita ; Barbato, Francesco ; Roberto, Marcello ; Guarino, Maria ; Asioli, Gian Maria ; Arpinati, Mario ; Cortelli, Pietro ; Maffini, Enrico ; Tomassini, Enrica ; Tassoni, Marta ; Cavallo, Carola ; Iannotta, Francesco ; Naddeo, Maria ; Tazzari, Pier Luigi ; Dan, Elisa ; Pellegrini, Cinzia ; Guadagnuolo, Serafina ; Carella, Matteo ; Sinigaglia, Barbara ; Pirazzini, Chiara ; Severi, Caterina ; Garagnani, Paolo ; Kwiatkowska, Katarzyna Malgorzata ; Ferracin, Manuela ; Zinzani, Pier Luigi ; Bonafè, Massimiliano ; Bonifazi, 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immunology</topic><topic>Lymphoma, B-Cell - therapy</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Nanoparticles</topic><topic>Neurotoxicity</topic><topic>Pathogenesis</topic><topic>Patients</topic><topic>Plasma</topic><topic>Pluripotency</topic><topic>Prospective Studies</topic><topic>Receptors, Chimeric Antigen - immunology</topic><topic>Stem cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Storci, Gianluca</creatorcontrib><creatorcontrib>De Felice, Francesco</creatorcontrib><creatorcontrib>Ricci, Francesca</creatorcontrib><creatorcontrib>Santi, Spartaco</creatorcontrib><creatorcontrib>Messelodi, Daria</creatorcontrib><creatorcontrib>Bertuccio, Salvatore Nicola</creatorcontrib><creatorcontrib>Laprovitera, Noemi</creatorcontrib><creatorcontrib>Dicataldo, Michele</creatorcontrib><creatorcontrib>Rossini, Lucrezia</creatorcontrib><creatorcontrib>De Matteis, Serena</creatorcontrib><creatorcontrib>Casadei, 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Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Storci, Gianluca</au><au>De Felice, Francesco</au><au>Ricci, Francesca</au><au>Santi, Spartaco</au><au>Messelodi, Daria</au><au>Bertuccio, Salvatore Nicola</au><au>Laprovitera, Noemi</au><au>Dicataldo, Michele</au><au>Rossini, Lucrezia</au><au>De Matteis, Serena</au><au>Casadei, Beatrice</au><au>Vaglio, Francesca</au><au>Ursi, Margherita</au><au>Barbato, Francesco</au><au>Roberto, Marcello</au><au>Guarino, Maria</au><au>Asioli, Gian Maria</au><au>Arpinati, Mario</au><au>Cortelli, Pietro</au><au>Maffini, Enrico</au><au>Tomassini, Enrica</au><au>Tassoni, Marta</au><au>Cavallo, Carola</au><au>Iannotta, Francesco</au><au>Naddeo, Maria</au><au>Tazzari, Pier Luigi</au><au>Dan, Elisa</au><au>Pellegrini, Cinzia</au><au>Guadagnuolo, Serafina</au><au>Carella, Matteo</au><au>Sinigaglia, Barbara</au><au>Pirazzini, Chiara</au><au>Severi, Caterina</au><au>Garagnani, Paolo</au><au>Kwiatkowska, Katarzyna Malgorzata</au><au>Ferracin, Manuela</au><au>Zinzani, Pier Luigi</au><au>Bonafè, Massimiliano</au><au>Bonifazi, Francesca</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2024-07-15</date><risdate>2024</risdate><volume>134</volume><issue>14</issue><spage>1</spage><epage>16</epage><pages>1-16</pages><issn>1558-8238</issn><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/μL at hour +1 or greater than 224.5 CAR+EVs/μL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>38833312</pmid><doi>10.1172/JCI173096</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-1536-5024</orcidid><orcidid>https://orcid.org/0000-0001-9856-7053</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1558-8238 |
| ispartof | The Journal of clinical investigation, 2024-07, Vol.134 (14), p.1-16 |
| issn | 1558-8238 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3064922388 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Adult Aged Antigen-presenting cells Antigens, CD19 - immunology B-cell lymphoma Biomarkers CD19 antigen Cell activation Convulsions & seizures Ecosystem recovery Edema Effector cells Extracellular vesicles Extracellular Vesicles - immunology Extracellular Vesicles - metabolism Female Humans Immunotherapy, Adoptive Lymphocytes Lymphocytes T Lymphoma Lymphoma, B-Cell - blood Lymphoma, B-Cell - immunology Lymphoma, B-Cell - therapy Male Middle Aged Nanoparticles Neurotoxicity Pathogenesis Patients Plasma Pluripotency Prospective Studies Receptors, Chimeric Antigen - immunology Stem cells |
| title | CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-15T22%3A52%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=CAR+%20extracellular%20vesicles%20predict%20ICANS%20in%20patients%20with%20B%20cell%20lymphomas%20treated%20with%20CD19-directed%20CAR%20T%20cells&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Storci,%20Gianluca&rft.date=2024-07-15&rft.volume=134&rft.issue=14&rft.spage=1&rft.epage=16&rft.pages=1-16&rft.issn=1558-8238&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI173096&rft_dat=%3Cproquest_cross%3E3089909190%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3089909190&rft_id=info:pmid/38833312&rfr_iscdi=true |