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2. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA)

Author

Hayden, P.J., Roddie, C., Bader, P., Basak, G.W., Bonig, H., Bonini, C., Chabannon, C., Ciceri, F., Corbacioglu, S., Ellard, R., Sanchez-Guijo, F., Jäger, U., Hildebrandt, M., Hudecek, M., Kersten, M.J., Köhl, U., Kuball, J., Mielke, S., Mohty, M., Murray, J., Nagler, A., Rees, J., Rioufol, C., Saccardi, R., Snowden, J.A., Styczynski, J., Subklewe, M., Thieblemont, C., Topp, M., Ispizua, Á.U., Chen, D., Vrhovac, R., Gribben, J.G., Kröger, N., Einsele, H., and Yakoub-Agha, I.

Published
2022
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3. Integrating biological HLA-DPB1 mismatch models to predict survival after unrelated hematopoietic cell transplantation

Author

Ruggeri, A, de Wreede, L, Muller, C, Crivello, P, Bonneville, E, Petersdorf, E, Socie, G, Dubois, V, Niittyvuopio, R, Perasaari, J, Yakoub-Agha, I, Cornelissen, J, Wieten, L, Gedde-Dahl, T, Forcade, E, Crawley, C, Marsh, S, Gandemer, V, Tholouli, E, Bulabois, C, Huynh, A, Choi, G, Deconinck, E, Itala-Remes, M, Lenhoff, S, Bengtsson, M, Johansson, J, van Gorkom, G, Hoogenboom, J, Vago, L, Rocha, V, Bonini, C, Chabannon, C, Fleischhauer, K, Clausen, J, Holter, W, Kalhs, P, Beguin, Y, Bron, D, Deeren, D, Lung, W, Kerre, T, Poire, X, Selleslag, D, Schroyens, W, Jindra, P, Mayer, J, Vydra, J, Zak, P, Nielsen, B, Sengeloev, H, Kaare, A, Partanen, A, Bay, J, Bertrand, Y, Blaise, D, Bourhis, J, Chevallier, P, Cluzeau, T, Damaj, G, Fegueux, N, Guyotat, D, Hunault-Berger, M, Labussiere-Wallet, H, Leleu, X, Lioure, B, Maury, S, Michel, G, Mohty, M, Rubio, M, Tilly, H, Turlure, P, Bethge, W, Casper, J, Einsele, H, Ganser, A, Kroger, N, Martin, S, Platzbecker, U, Reinhardt, C, Schafer-Eckart, K, Thurner, L, Valerius, T, Wulf, G, Karakasis, D, Spyridonidis, A, Hauser, P, Remenyi, P, Reykdal, S, Mousavi, A, Angelucci, E, Arcese, W, Benedetti, F, Bernasconi, P, Biondi, A, Bonifazi, F, Carella, A, Carluccio, P, Casini, M, Cavanna, L, Ciceri, F, Cimino, G, Corradini, P, Fanin, R, Galieni, P, Grillo, G, Iori, A, La Nasa, G, Locatelli, F, Marotta, G, Martino, M, Mazza, P, Mordini, N, Musso, M, Olivieri, A, Pavone, V, Pane, F, Petrini, M, Pioltelli, P, Rambaldi, A, Ruggeri, M, Saccardi, R, Santarone, S, Scime, R, Sica, S, Tarella, C, Velardi, A, Visani, G, Zecca, M, Tanase, A, Kulagin, A, Savchenko, V, Lopez, C, Amor, A, Lopez, J, Caballero, D, Duarte, R, Cascon, M, Porras, R, Perez-Simon, J, Rovira, M, Sanz, J, Carrete, J, Cammenga, J, Isaksson, C, Mielke, S, Chalandon, Y, Passweg, J, Schanz, U, Meijer, E, Kuball, J, Veelken, J, Apperley, J, Bloor, A, Byrne, J, Carpenter, B, Clark, A, Collin, M, Craddock, C, Gibson, B, Khan, A, Martin, M, Medd, P, Nicholson, E, Orchard, K, Patel, A, Peniket, A, Potter, V, Snowden, J, Wilson, K, Ruggeri A., de Wreede L. C., Muller C. R., Crivello P., Bonneville E. F., Petersdorf E. W., Socie G., Dubois V., Niittyvuopio R., Perasaari J., Yakoub-Agha I., Cornelissen J. J., Wieten L., Gedde-Dahl T., Forcade E., Crawley C. R., Marsh S. G. E., Gandemer V., Tholouli E., Bulabois C. -E., Huynh A., Choi G., Deconinck E., Itala-Remes M., Lenhoff S., Bengtsson M., Johansson J. -E., van Gorkom G., Hoogenboom J. D., Vago L., Rocha V., Bonini C., Chabannon C., Fleischhauer K., Clausen J., Holter W., Kalhs P., Beguin Y., Bron D., Deeren D., Lung W. K., Kerre T., Poire X., Selleslag D., Schroyens W., Jindra P., Mayer J., Vydra J., Zak P., Nielsen B., Sengeloev H., Kaare A., Partanen A., Bay J., Bertrand Y., Blaise D., Bourhis J. H., Chevallier P., Cluzeau T., Damaj G., Fegueux N., Guyotat D., Hunault-Berger M., Labussiere-Wallet H., Leleu X., Lioure B., Maury S., Michel G., Mohty M., Rubio M. T., Tilly H., Turlure P., Bethge W., Casper J., Einsele H., Ganser A., Kroger N., Martin S., Platzbecker U., Reinhardt C., Schafer-Eckart K., Thurner L., Valerius T., Wulf G. G., Karakasis D., Spyridonidis A., Hauser P., Remenyi P., Reykdal S., Mousavi A., Angelucci E., Arcese W., Benedetti F., Bernasconi P., Biondi A., Bonifazi F., Carella A. M., Carluccio P., Casini M., Cavanna L., Ciceri F., Cimino G., Corradini P., Fanin R., Galieni P., Grillo G., Iori A. P., La Nasa G., Locatelli F., Marotta G., Martino M., Mazza P., Mordini N., Musso M., Olivieri A., Pavone V., Pane F., Petrini M., Pioltelli P., Rambaldi A., Ruggeri M., Saccardi R., Santarone S., Scime R., Sica S., Tarella C., Velardi A., Visani G., Zecca M., Tanase A., Kulagin A., Savchenko V., Lopez C. A., Amor A. A., Lopez J. L. B., Caballero D., Duarte R., Cascon M. J. P., Porras R. P., Perez-Simon J. A., Rovira M., Sanz J., Carrete J. P. T., Cammenga J., Isaksson C., Mielke S., Chalandon Y., Passweg J., Schanz U., Meijer E., Kuball J., Veelken J. H., Apperley J., Bloor A., Byrne J., Carpenter B., Clark A., Collin M., Craddock C., Gibson B. E., Khan A., Martin M., Medd P., Nicholson E., Orchard K., Patel A., Peniket A., Potter V., Snowden J., Wilson K. M. O., Ruggeri, A, de Wreede, L, Muller, C, Crivello, P, Bonneville, E, Petersdorf, E, Socie, G, Dubois, V, Niittyvuopio, R, Perasaari, J, Yakoub-Agha, I, Cornelissen, J, Wieten, L, Gedde-Dahl, T, Forcade, E, Crawley, C, Marsh, S, Gandemer, V, Tholouli, E, Bulabois, C, Huynh, A, Choi, G, Deconinck, E, Itala-Remes, M, Lenhoff, S, Bengtsson, M, Johansson, J, van Gorkom, G, Hoogenboom, J, Vago, L, Rocha, V, Bonini, C, Chabannon, C, Fleischhauer, K, Clausen, J, Holter, W, Kalhs, P, Beguin, Y, Bron, D, Deeren, D, Lung, W, Kerre, T, Poire, X, Selleslag, D, Schroyens, W, Jindra, P, Mayer, J, Vydra, J, Zak, P, Nielsen, B, Sengeloev, H, Kaare, A, Partanen, A, Bay, J, Bertrand, Y, Blaise, D, Bourhis, J, Chevallier, P, Cluzeau, T, Damaj, G, Fegueux, N, Guyotat, D, Hunault-Berger, M, Labussiere-Wallet, H, Leleu, X, Lioure, B, Maury, S, Michel, G, Mohty, M, Rubio, M, Tilly, H, Turlure, P, Bethge, W, Casper, J, Einsele, H, Ganser, A, Kroger, N, Martin, S, Platzbecker, U, Reinhardt, C, Schafer-Eckart, K, Thurner, L, Valerius, T, Wulf, G, Karakasis, D, Spyridonidis, A, Hauser, P, Remenyi, P, Reykdal, S, Mousavi, A, Angelucci, E, Arcese, W, Benedetti, F, Bernasconi, P, Biondi, A, Bonifazi, F, Carella, A, Carluccio, P, Casini, M, Cavanna, L, Ciceri, F, Cimino, G, Corradini, P, Fanin, R, Galieni, P, Grillo, G, Iori, A, La Nasa, G, Locatelli, F, Marotta, G, Martino, M, Mazza, P, Mordini, N, Musso, M, Olivieri, A, Pavone, V, Pane, F, Petrini, M, Pioltelli, P, Rambaldi, A, Ruggeri, M, Saccardi, R, Santarone, S, Scime, R, Sica, S, Tarella, C, Velardi, A, Visani, G, Zecca, M, Tanase, A, Kulagin, A, Savchenko, V, Lopez, C, Amor, A, Lopez, J, Caballero, D, Duarte, R, Cascon, M, Porras, R, Perez-Simon, J, Rovira, M, Sanz, J, Carrete, J, Cammenga, J, Isaksson, C, Mielke, S, Chalandon, Y, Passweg, J, Schanz, U, Meijer, E, Kuball, J, Veelken, J, Apperley, J, Bloor, A, Byrne, J, Carpenter, B, Clark, A, Collin, M, Craddock, C, Gibson, B, Khan, A, Martin, M, Medd, P, Nicholson, E, Orchard, K, Patel, A, Peniket, A, Potter, V, Snowden, J, Wilson, K, Ruggeri A., de Wreede L. C., Muller C. R., Crivello P., Bonneville E. F., Petersdorf E. W., Socie G., Dubois V., Niittyvuopio R., Perasaari J., Yakoub-Agha I., Cornelissen J. J., Wieten L., Gedde-Dahl T., Forcade E., Crawley C. R., Marsh S. G. E., Gandemer V., Tholouli E., Bulabois C. -E., Huynh A., Choi G., Deconinck E., Itala-Remes M., Lenhoff S., Bengtsson M., Johansson J. -E., van Gorkom G., Hoogenboom J. D., Vago L., Rocha V., Bonini C., Chabannon C., Fleischhauer K., Clausen J., Holter W., Kalhs P., Beguin Y., Bron D., Deeren D., Lung W. K., Kerre T., Poire X., Selleslag D., Schroyens W., Jindra P., Mayer J., Vydra J., Zak P., Nielsen B., Sengeloev H., Kaare A., Partanen A., Bay J., Bertrand Y., Blaise D., Bourhis J. H., Chevallier P., Cluzeau T., Damaj G., Fegueux N., Guyotat D., Hunault-Berger M., Labussiere-Wallet H., Leleu X., Lioure B., Maury S., Michel G., Mohty M., Rubio M. T., Tilly H., Turlure P., Bethge W., Casper J., Einsele H., Ganser A., Kroger N., Martin S., Platzbecker U., Reinhardt C., Schafer-Eckart K., Thurner L., Valerius T., Wulf G. G., Karakasis D., Spyridonidis A., Hauser P., Remenyi P., Reykdal S., Mousavi A., Angelucci E., Arcese W., Benedetti F., Bernasconi P., Biondi A., Bonifazi F., Carella A. M., Carluccio P., Casini M., Cavanna L., Ciceri F., Cimino G., Corradini P., Fanin R., Galieni P., Grillo G., Iori A. P., La Nasa G., Locatelli F., Marotta G., Martino M., Mazza P., Mordini N., Musso M., Olivieri A., Pavone V., Pane F., Petrini M., Pioltelli P., Rambaldi A., Ruggeri M., Saccardi R., Santarone S., Scime R., Sica S., Tarella C., Velardi A., Visani G., Zecca M., Tanase A., Kulagin A., Savchenko V., Lopez C. A., Amor A. A., Lopez J. L. B., Caballero D., Duarte R., Cascon M. J. P., Porras R. P., Perez-Simon J. A., Rovira M., Sanz J., Carrete J. P. T., Cammenga J., Isaksson C., Mielke S., Chalandon Y., Passweg J., Schanz U., Meijer E., Kuball J., Veelken J. H., Apperley J., Bloor A., Byrne J., Carpenter B., Clark A., Collin M., Craddock C., Gibson B. E., Khan A., Martin M., Medd P., Nicholson E., Orchard K., Patel A., Peniket A., Potter V., Snowden J., and Wilson K. M. O.

Published
2023

7. POS1418 ANTIGEN-SPECIFIC T-CELL DYNAMICS AND MULTIDIRECTIONAL IMMUNE DYSREGULATION IN SLE

Author

Ramirez, G. A., primary, Tassi, E., additional, Noviello, M., additional, Mazzi, B. A., additional, Moroni, L., additional, Sorce, A., additional, Citterio, L., additional, Zagato, L., additional, Tombetti, E., additional, Baldissera, E., additional, Colombo, G., additional, Yacoub, M. R., additional, Bozzolo, E., additional, Bonini, C., additional, Dagna, L., additional, and Manfredi, A., additional

Published
2023
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8. POS1432 CAR-TREGS FOR SYSTEMIC LUPUS ERYTHEMATOSUS

Author

Doglio, M., primary, Ugolini, A., additional, Camisa, B., additional, Toma, C., additional, Norata, R., additional, Del Rosso, S., additional, Ciceri, F., additional, Sanvito, F., additional, Casucci, M., additional, Manfredi, A., additional, and Bonini, C., additional

Published
2023
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11. Immune effector cell–associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations

Author

Rejeski, K, Subklewe, M, Aljurf, M, Bachy, E, Balduzzi, A, Barba, P, Bruno, B, Benjamin, R, Carrabba, M, Chabannon, C, Ciceri, F, Corradini, P, Delgado, J, Di Blasi, R, Greco, R, Houot, R, Iacoboni, G, Jaeger, U, Kersten, M, Mielke, S, Nagler, A, Onida, F, Peric, Z, Roddie, C, Ruggeri, A, Sanchez-Guijo, F, Sánchez-Ortega, I, Schneidawind, D, Schubert, M, Snowden, J, Thieblemont, C, Topp, M, Zinzani, P, Gribben, J, Bonini, C, Sureda Balari, A, Yakoub-Agha, I, Rejeski, Kai, Subklewe, Marion, Aljurf, Mahmoud, Bachy, Emmanuel, Balduzzi, Adriana Cristina, Barba, Pere, Bruno, Benedetto, Benjamin, Reuben, Carrabba, Matteo Giovanni, Chabannon, Christian, Ciceri, Fabio, Corradini, Paolo, Delgado, Julio, Di Blasi, Roberta, Greco, Raffaella, Houot, Roch, Iacoboni, Gloria, Jaeger, Ulrich, Kersten, Marie José, Mielke, Stephan, Nagler, Arnon, Onida, Francesco, Peric, Zinaida, Roddie, Claire, Ruggeri, Annalisa, Sanchez-Guijo, Fermin M, Sánchez-Ortega, Isabel, Schneidawind, Dominik, Schubert, Maria-Luisa, Snowden, John, Thieblemont, Catherine, Topp, Max S, Zinzani, Pierluigi Luigi, Gribben, John G, Bonini, Chiara, Sureda Balari, Anna, Yakoub-Agha, Ibrahim, Rejeski, K, Subklewe, M, Aljurf, M, Bachy, E, Balduzzi, A, Barba, P, Bruno, B, Benjamin, R, Carrabba, M, Chabannon, C, Ciceri, F, Corradini, P, Delgado, J, Di Blasi, R, Greco, R, Houot, R, Iacoboni, G, Jaeger, U, Kersten, M, Mielke, S, Nagler, A, Onida, F, Peric, Z, Roddie, C, Ruggeri, A, Sanchez-Guijo, F, Sánchez-Ortega, I, Schneidawind, D, Schubert, M, Snowden, J, Thieblemont, C, Topp, M, Zinzani, P, Gribben, J, Bonini, C, Sureda Balari, A, Yakoub-Agha, I, Rejeski, Kai, Subklewe, Marion, Aljurf, Mahmoud, Bachy, Emmanuel, Balduzzi, Adriana Cristina, Barba, Pere, Bruno, Benedetto, Benjamin, Reuben, Carrabba, Matteo Giovanni, Chabannon, Christian, Ciceri, Fabio, Corradini, Paolo, Delgado, Julio, Di Blasi, Roberta, Greco, Raffaella, Houot, Roch, Iacoboni, Gloria, Jaeger, Ulrich, Kersten, Marie José, Mielke, Stephan, Nagler, Arnon, Onida, Francesco, Peric, Zinaida, Roddie, Claire, Ruggeri, Annalisa, Sanchez-Guijo, Fermin M, Sánchez-Ortega, Isabel, Schneidawind, Dominik, Schubert, Maria-Luisa, Snowden, John, Thieblemont, Catherine, Topp, Max S, Zinzani, Pierluigi Luigi, Gribben, John G, Bonini, Chiara, Sureda Balari, Anna, and Yakoub-Agha, Ibrahim

Abstract

Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell–associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management.

Published
2023

12. Gut virome-colonising Orthohepadnavirus genus is associated with ulcerative colitis pathogenesis and induces intestinal inflammation in vivo

Author

Massimino, L, Palmieri, O, Facoetti, A, Fuggetta, D, Spanò, S, Lamparelli, L, D'Alessio, S, Cagliani, S, Furfaro, F, D'Amico, F, Zilli, A, Fiorino, G, Parigi, T, Noviello, D, Latiano, A, Bossa, F, Latiano, T, Pirola, A, Mologni, L, Piazza, R, Abbati, D, Perri, F, Bonini, C, Peyrin-Biroulet, L, Malesci, A, Jairath, V, Danese, S, Ungaro, F, Massimino, Luca, Palmieri, Orazio, Facoetti, Amanda, Fuggetta, Davide, Spanò, Salvatore, Lamparelli, Luigi Antonio, D'Alessio, Silvia, Cagliani, Stefania, Furfaro, Federica, D'Amico, Ferdinando, Zilli, Alessandra, Fiorino, Gionata, Parigi, Tommaso Lorenzo, Noviello, Daniele, Latiano, Anna, Bossa, Fabrizio, Latiano, Tiziana, Pirola, Alessandra, Mologni, Luca, Piazza, Rocco Giovanni, Abbati, Danilo, Perri, Francesco, Bonini, Chiara, Peyrin-Biroulet, Laurent, Malesci, Alberto, Jairath, Vipul, Danese, Silvio, Ungaro, Federica, Massimino, L, Palmieri, O, Facoetti, A, Fuggetta, D, Spanò, S, Lamparelli, L, D'Alessio, S, Cagliani, S, Furfaro, F, D'Amico, F, Zilli, A, Fiorino, G, Parigi, T, Noviello, D, Latiano, A, Bossa, F, Latiano, T, Pirola, A, Mologni, L, Piazza, R, Abbati, D, Perri, F, Bonini, C, Peyrin-Biroulet, L, Malesci, A, Jairath, V, Danese, S, Ungaro, F, Massimino, Luca, Palmieri, Orazio, Facoetti, Amanda, Fuggetta, Davide, Spanò, Salvatore, Lamparelli, Luigi Antonio, D'Alessio, Silvia, Cagliani, Stefania, Furfaro, Federica, D'Amico, Ferdinando, Zilli, Alessandra, Fiorino, Gionata, Parigi, Tommaso Lorenzo, Noviello, Daniele, Latiano, Anna, Bossa, Fabrizio, Latiano, Tiziana, Pirola, Alessandra, Mologni, Luca, Piazza, Rocco Giovanni, Abbati, Danilo, Perri, Francesco, Bonini, Chiara, Peyrin-Biroulet, Laurent, Malesci, Alberto, Jairath, Vipul, Danese, Silvio, and Ungaro, Federica

Abstract

Objectives: Ulcerative colitis (UC) is a chronic inflammatory disorder of unknown aetiology. Gut virome dysbiosis is fundamental in UC progression, although its role in the early phases of the disease is far from fully understood. Therefore, we sought to investigate the role of a virome-associated protein encoded by the Orthohepadnavirus genus, the hepatitis B virus X protein (HBx), in UC aetiopathogenesis. Design: HBx positivity of UC patient-derived blood and gut mucosa was assessed by RT-PCR and Sanger sequencing and correlated with clinical characteristics by multivariate analysis. Transcriptomics was performed on HBx-overexpressing endoscopic biopsies from healthy donors. C57BL/6 mice underwent intramucosal injections of liposome-conjugated HBx-encoding plasmids or the control, with or without antibiotic treatment. Multidimensional flow cytometry analysis was performed on colonic samples from HBx-treated and control animals. Transepithelial electrical resistance measurement, proliferation assay, chromatin immunoprecipitation assay with sequencing and RNA-sequencing were performed on in vitro models of the gut barrier. HBx-silencing experiments were performed in vitro and in vivo. Results: HBx was detected in about 45% of patients with UC and found to induce colonic inflammation in mice, while its silencing reverted the colitis phenotype in vivo. HBx acted as a transcriptional regulator in epithelial cells, provoking barrier leakage and altering both innate and adaptive mucosal immunity ex vivo and in vivo. Conclusion: This study described HBx as a contributor to the UC pathogenesis and provides a new perspective on the virome as a target for tailored treatments.

Published
2023

13. Integrating biological HLA-DPB1 mismatch models to predict survival after unrelated hematopoietic cell transplantation

Author

Ruggeri, A., de Wreede, L. C., Muller, C. R., Crivello, P., Bonneville, E. F., Petersdorf, E. W., Socie, G., Dubois, V., Niittyvuopio, R., Perasaari, J., Yakoub-Agha, I., Cornelissen, J. J., Wieten, L., Gedde-Dahl, T., Forcade, E., Crawley, C. R., Marsh, S. G. E., Gandemer, V., Tholouli, E., Bulabois, C. -E., Huynh, A., Choi, G., Deconinck, E., Itala-Remes, M., Lenhoff, S., Bengtsson, M., Johansson, J. -E., van Gorkom, G., Hoogenboom, J. D., Vago, L., Rocha, V., Bonini, C., Chabannon, C., Fleischhauer, K., Clausen, J., Holter, W., Kalhs, P., Beguin, Y., Bron, D., Deeren, D., Lung, W. K., Kerre, T., Poire, X., Selleslag, D., Schroyens, W., Jindra, P., Mayer, J., Vydra, J., Zak, P., Nielsen, B., Sengeloev, H., Kaare, A., Partanen, A., Bay, J., Bertrand, Y., Blaise, D., Bourhis, J. H., Chevallier, P., Cluzeau, T., Damaj, G., Fegueux, N., Guyotat, D., Hunault-Berger, M., Labussiere-Wallet, H., Leleu, X., Lioure, B., Maury, S., Michel, G., Mohty, M., Rubio, M. T., Tilly, H., Turlure, P., Bethge, W., Casper, J., Einsele, H., Ganser, A., Kroger, N., Martin, S., Platzbecker, U., Reinhardt, C., Schafer-Eckart, K., Thurner, L., Valerius, T., Wulf, G. G., Karakasis, D., Spyridonidis, A., Hauser, P., Remenyi, P., Reykdal, S., Mousavi, A., Angelucci, E., Arcese, W., Benedetti, F., Bernasconi, P., Biondi, A., Bonifazi, F., Carella, A. M., Carluccio, P., Casini, M., Cavanna, L., Ciceri, F., Cimino, G., Corradini, P., Fanin, R., Galieni, P., Grillo, G., Iori, A. P., La Nasa, G., Locatelli, Franco, Marotta, G., Martino, M., Mazza, P., Mordini, N., Musso, M., Olivieri, A., Pavone, V., Pane, F., Petrini, M., Pioltelli, P., Rambaldi, A., Ruggeri, M., Saccardi, R., Santarone, S., Scime, R., Sica, S., Tarella, C., Velardi, A., Visani, G., Zecca, M., Tanase, A., Kulagin, A., Savchenko, V., Lopez, C. A., Amor, A. A., Lopez, J. L. B., Caballero, D., Duarte, R., Cascon, M. J. P., Porras, R. P., Perez-Simon, J. A., Rovira, M., Sanz, J., Carrete, J. P. T., Cammenga, J., Isaksson, C., Mielke, S., Chalandon, Y., Passweg, J., Schanz, U., Meijer, E., Kuball, J., Veelken, J. H., Apperley, J., Bloor, A., Byrne, J., Carpenter, B., Clark, A., Collin, M., Craddock, C., Gibson, B. E., Khan, A., Martin, M., Medd, P., Nicholson, E., Orchard, K., Patel, A., Peniket, A., Potter, V., Snowden, J., Wilson, K. M. O., Locatelli F. (ORCID:0000-0002-7976-3654), Ruggeri, A., de Wreede, L. C., Muller, C. R., Crivello, P., Bonneville, E. F., Petersdorf, E. W., Socie, G., Dubois, V., Niittyvuopio, R., Perasaari, J., Yakoub-Agha, I., Cornelissen, J. J., Wieten, L., Gedde-Dahl, T., Forcade, E., Crawley, C. R., Marsh, S. G. E., Gandemer, V., Tholouli, E., Bulabois, C. -E., Huynh, A., Choi, G., Deconinck, E., Itala-Remes, M., Lenhoff, S., Bengtsson, M., Johansson, J. -E., van Gorkom, G., Hoogenboom, J. D., Vago, L., Rocha, V., Bonini, C., Chabannon, C., Fleischhauer, K., Clausen, J., Holter, W., Kalhs, P., Beguin, Y., Bron, D., Deeren, D., Lung, W. K., Kerre, T., Poire, X., Selleslag, D., Schroyens, W., Jindra, P., Mayer, J., Vydra, J., Zak, P., Nielsen, B., Sengeloev, H., Kaare, A., Partanen, A., Bay, J., Bertrand, Y., Blaise, D., Bourhis, J. H., Chevallier, P., Cluzeau, T., Damaj, G., Fegueux, N., Guyotat, D., Hunault-Berger, M., Labussiere-Wallet, H., Leleu, X., Lioure, B., Maury, S., Michel, G., Mohty, M., Rubio, M. T., Tilly, H., Turlure, P., Bethge, W., Casper, J., Einsele, H., Ganser, A., Kroger, N., Martin, S., Platzbecker, U., Reinhardt, C., Schafer-Eckart, K., Thurner, L., Valerius, T., Wulf, G. G., Karakasis, D., Spyridonidis, A., Hauser, P., Remenyi, P., Reykdal, S., Mousavi, A., Angelucci, E., Arcese, W., Benedetti, F., Bernasconi, P., Biondi, A., Bonifazi, F., Carella, A. M., Carluccio, P., Casini, M., Cavanna, L., Ciceri, F., Cimino, G., Corradini, P., Fanin, R., Galieni, P., Grillo, G., Iori, A. P., La Nasa, G., Locatelli, Franco, Marotta, G., Martino, M., Mazza, P., Mordini, N., Musso, M., Olivieri, A., Pavone, V., Pane, F., Petrini, M., Pioltelli, P., Rambaldi, A., Ruggeri, M., Saccardi, R., Santarone, S., Scime, R., Sica, S., Tarella, C., Velardi, A., Visani, G., Zecca, M., Tanase, A., Kulagin, A., Savchenko, V., Lopez, C. A., Amor, A. A., Lopez, J. L. B., Caballero, D., Duarte, R., Cascon, M. J. P., Porras, R. P., Perez-Simon, J. A., Rovira, M., Sanz, J., Carrete, J. P. T., Cammenga, J., Isaksson, C., Mielke, S., Chalandon, Y., Passweg, J., Schanz, U., Meijer, E., Kuball, J., Veelken, J. H., Apperley, J., Bloor, A., Byrne, J., Carpenter, B., Clark, A., Collin, M., Craddock, C., Gibson, B. E., Khan, A., Martin, M., Medd, P., Nicholson, E., Orchard, K., Patel, A., Peniket, A., Potter, V., Snowden, J., Wilson, K. M. O., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2023

14. OP32 The gut virome-colonizing Orthohepadnavirus genus is associated with ulcerative colitis pathogenesis and induces intestinal inflammation in vivo

Author

Facoetti, A, primary, Massimino, L, additional, Palmieri, O, additional, Fuggetta, D, additional, Spanò, S, additional, D'Alessio, S, additional, Furfaro, F, additional, D'Amico, F, additional, ZIlli, A, additional, Fiorino, G, additional, Noviello, D, additional, Latiano, A, additional, Bossa, F, additional, Pirola, A, additional, Mologni, L, additional, Piazza, R, additional, Abbati, D, additional, Perri, F, additional, Bonini, C, additional, Peyrin-Biroulet, L, additional, Malesci, A, additional, Danese, S, additional, and Ungaro, F, additional

Published
2023
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17. Human T cells engineered with a leukemia lipid-specific TCR enables donor-unrestricted recognition of CD1c-expressing leukemia

Author

Consonni, M, Garavaglia, C, Grilli, A, de Lalla, C, Mancino, A, Mori, L, De Libero, G, Montagna, D, Casucci, M, Serafini, M, Bonini, C, Häussinger, D, Ciceri, F, Bernardi, M, Mastaglio, S, Bicciato, S, Dellabona, P, Casorati, G, Consonni M, Garavaglia C, Grilli A, de Lalla C, Mancino A, Mori L, De Libero G, Montagna D, Casucci M, Serafini M, Bonini C, Häussinger D, Ciceri F, Bernardi M, Mastaglio S, Bicciato S, Dellabona P, Casorati G, Consonni, M, Garavaglia, C, Grilli, A, de Lalla, C, Mancino, A, Mori, L, De Libero, G, Montagna, D, Casucci, M, Serafini, M, Bonini, C, Häussinger, D, Ciceri, F, Bernardi, M, Mastaglio, S, Bicciato, S, Dellabona, P, Casorati, G, Consonni M, Garavaglia C, Grilli A, de Lalla C, Mancino A, Mori L, De Libero G, Montagna D, Casucci M, Serafini M, Bonini C, Häussinger D, Ciceri F, Bernardi M, Mastaglio S, Bicciato S, Dellabona P, and Casorati G

Abstract

Acute leukemia relapsing after chemotherapy plus allogeneic hematopoietic stem cell transplantation can be treated with donor-derived T cells, but this is hampered by the need for donor/recipient MHC-matching and often results in graft-versus-host disease, prompting the search for new donor-unrestricted strategies targeting malignant cells. Leukemia blasts express CD1c antigen-presenting molecules, which are identical in all individuals and expressed only by mature leukocytes, and are recognized by T cell clones specific for the CD1c-restricted leukemia-associated methyl-lysophosphatidic acid (mLPA) lipid antigen. Here, we show that human T cells engineered to express an mLPA-specific TCR, target diverse CD1c-expressing leukemia blasts in vitro and significantly delay the progression of three models of leukemia xenograft in NSG mice, an effect that is boosted by mLPA-cellular immunization. These results highlight a strategy to redirect T cells against leukemia via transfer of a lipid-specific TCR that could be used across MHC barriers with reduced risk of graft-versus-host disease.

Published
2021

20. Time to evolve: predicting engineered T cell-associated toxicity with next-generation models

Author

Donnadieu, E., Luu, M., Alb, M., Anliker, B., Arcangeli, S., Bonini, C., De Angelis, B., Choudhary, R., Espie, D., Galy, A., Holland, C., Ivics, Z., Kantari-Mimoun, C., Kersten, M. J., Kohl, U., Kuhn, C., Laugel, B., Locatelli, Franco, Marchiq, I., Markman, J., Moresco, M. A., Morris, E., Negre, H., Quintarelli, C., Rade, M., Reiche, K., Renner, M., Ruggiero, E., Sanges, C., Stauss, H., Themeli, M., Van den Brulle, J., Hudecek, M., Casucci, M., Locatelli F. (ORCID:0000-0002-7976-3654), Donnadieu, E., Luu, M., Alb, M., Anliker, B., Arcangeli, S., Bonini, C., De Angelis, B., Choudhary, R., Espie, D., Galy, A., Holland, C., Ivics, Z., Kantari-Mimoun, C., Kersten, M. J., Kohl, U., Kuhn, C., Laugel, B., Locatelli, Franco, Marchiq, I., Markman, J., Moresco, M. A., Morris, E., Negre, H., Quintarelli, C., Rade, M., Reiche, K., Renner, M., Ruggiero, E., Sanges, C., Stauss, H., Themeli, M., Van den Brulle, J., Hudecek, M., Casucci, M., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, including humanized mouse models, which can better recapitulate toxicities observed in patients. The Accelerating Development and Improving Access to CAR and TCR-engineered T cell therapy (T2EVOLVE) consortium is a public-private partnership directed at accelerating the preclinical development and increasing access to engineered T-cell therapy for patients with cancer. A key ambition in T2EVOLVE is to design new models and tools with higher predictive value for clinical safety and efficacy, in order to improve and accelerate the selection of lead T-cell products for clinical translation. Herein, we review existing preclinical models that are used to test the safety of engineered T cells. We will also highlight limitations of these models and propose potential measures to improve them.

Published
2022

21. Management of Adults and Children receiving CAR T-cell therapy: 2021 Best Practice Recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA)

Author

CTI Kuball, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Hayden, P J, Roddie, C, Bader, P, Basak, G W, Bonig, H, Bonini, C, Chabannon, C, Ciceri, F, Corbacioglu, S, Ellard, R, Sanchez-Guijo, F, Jäger, U, Hildebrandt, M, Hudecek, M, Kersten, M J, Köhl, U, Kuball, J, Mielke, S, Mohty, M, Murray, J, Nagler, A, Rees, J, Rioufol, C, Saccardi, R, Snowden, J A, Styczynski, J, Subklewe, M, Thieblemont, C, Topp, M, Ispizua, Á U, Chen, D, Vrhovac, R, Gribben, J G, Kröger, N, Einsele, H, Yakoub-Agha, I, CTI Kuball, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Hayden, P J, Roddie, C, Bader, P, Basak, G W, Bonig, H, Bonini, C, Chabannon, C, Ciceri, F, Corbacioglu, S, Ellard, R, Sanchez-Guijo, F, Jäger, U, Hildebrandt, M, Hudecek, M, Kersten, M J, Köhl, U, Kuball, J, Mielke, S, Mohty, M, Murray, J, Nagler, A, Rees, J, Rioufol, C, Saccardi, R, Snowden, J A, Styczynski, J, Subklewe, M, Thieblemont, C, Topp, M, Ispizua, Á U, Chen, D, Vrhovac, R, Gribben, J G, Kröger, N, Einsele, H, and Yakoub-Agha, I

Published
2022

22. Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients

Author

Arcangeli, S, Falcone, L, Camisa, B, De Girardi, F, Biondi, M, Giglio, F, Ciceri, F, Bonini, C, Bondanza, A, Casucci, M, Arcangeli S., Falcone L., Camisa B., De Girardi F., Biondi M., Giglio F., Ciceri F., Bonini C., Bondanza A., Casucci M., Arcangeli, S, Falcone, L, Camisa, B, De Girardi, F, Biondi, M, Giglio, F, Ciceri, F, Bonini, C, Bondanza, A, Casucci, M, Arcangeli S., Falcone L., Camisa B., De Girardi F., Biondi M., Giglio F., Ciceri F., Bonini C., Bondanza A., and Casucci M.

Abstract

Chimeric antigen receptor (CAR) T cell expansion and persistence emerged as key efficacy determinants in cancer patients. These features are typical of early-memory T cells, which can be enriched with specific manufacturing procedures, providing signal one and signal two in the proper steric conformation and in the presence of homeostatic cytokines. In this project, we exploited our expertise with paramagnetic beads and IL-7/IL-15 to develop an optimized protocol for CAR T cell production based on reagents, including a polymeric nanomatrix, which are compatible with automated manufacturing via the CliniMACS Prodigy. We found that both procedures generate similar CAR T cell products, highly enriched of stem cell memory T cells (TSCM) and equally effective in counteracting tumor growth in xenograft mouse models. Most importantly, the optimized protocol was able to expand CAR TSCM from B-cell acute lymphoblastic leukemia (B-ALL) patients, which in origin were highly enriched of late-memory and exhausted T cells. Notably, CAR T cells derived from B-ALL patients proved to be as efficient as healthy donor-derived CAR T cells in mediating profound and prolonged anti-tumor responses in xenograft mouse models. On the contrary, the protocol failed to expand fully functional CAR TSCM from patients with pancreatic ductal adenocarcinoma, suggesting that patient-specific factors may profoundly affect intrinsic T cell quality. Finally, by retrospective analysis of in vivo data, we observed that the proportion of TSCM in the final CAR T cell product positively correlated with in vivo expansion, which in turn proved to be crucial for achieving long-term remissions. Collectively, our data indicate that next-generation manufacturing protocols can overcome initial T cell defects, resulting in TSCM-enriched CAR T cell products qualitatively equivalent to the ones generated from healthy donors. However, this positive effect may be decreased in specific conditions, for which the developme

Published
2020

23. TCR Redirected T Cells for Cancer Treatment: Achievements, Hurdles, and Goals

Author

Manfredi, F, Cianciotti, B, Potenza, A, Tassi, E, Noviello, M, Biondi, A, Ciceri, F, Bonini, C, Ruggiero, E, Manfredi F., Cianciotti B. C., Potenza A., Tassi E., Noviello M., Biondi A., Ciceri F., Bonini C., Ruggiero E., Manfredi, F, Cianciotti, B, Potenza, A, Tassi, E, Noviello, M, Biondi, A, Ciceri, F, Bonini, C, Ruggiero, E, Manfredi F., Cianciotti B. C., Potenza A., Tassi E., Noviello M., Biondi A., Ciceri F., Bonini C., and Ruggiero E.

Abstract

Adoptive T cell therapy (ACT) is a rapidly evolving therapeutic approach designed to harness T cell specificity and function to fight diseases. Based on the evidence that T lymphocytes can mediate a potent anti-tumor response, initially ACT solely relied on the isolation, in vitro expansion, and infusion of tumor-infiltrating or circulating tumor-specific T cells. Although effective in a subset of cases, in the first ACT clinical trials several patients experienced disease progression, in some cases after temporary disease control. This evidence prompted researchers to improve ACT products by taking advantage of the continuously evolving gene engineering field and by improving manufacturing protocols, to enable the generation of effective and long-term persisting tumor-specific T cell products. Despite recent advances, several challenges, including prioritization of antigen targets, identification, and optimization of tumor-specific T cell receptors, in the development of tools enabling T cells to counteract the immunosuppressive tumor microenvironment, still need to be faced. This review aims at summarizing the major achievements, hurdles and possible solutions designed to improve the ACT efficacy and safety profile in the context of liquid and solid tumors.

Published
2020

24. Management of adults and children receiving CAR T- cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA)

Author

Hayden, PJ, Roddie, C, Bader, P, Basak, GW, Bonig, H, Bonini, C, Chabannon, C, Ciceri, F, Corbacioglu, S, Ellard, R, Sanchez-Guijo, F, Jäger, U, Hildebrandt, M, Hudecek, M, Kersten, MJ, Köhl, U, Kuball, J, Mielke, S, Mohty, M, Murray, J, Nagler, A, Rees, J, Rioufol, C, Saccardi, R, Snowden, JA, Styczynski, J, Subklewe, M, Thieblemont, C, Topp, M, Ispizua, ÁU, Chen, D, Vrhovac, Radovan, Gribben, JG, Kröger, N, Einsele, H, and Yakoub-Agha, I

Subjects
CAR T-cell therapy, best practice recommendations
Abstract

Background: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. Design: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. Results: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post- authorisation safety surveillance and regulatory issues. Conclusions: We provide practical, clinically relevant recommendations on the use of these high- cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic. Keywords: B-cell acute lymphoblastic leukemia (B ALL) ; CAR T-cells ; cytokine release syndrome (CRS) ; immune effector cell associated neurotoxicity syndrome (ICANS) ; large B-cell lymphoma (LBCL) ; multiple myeloma (MM).

Published
2022

27. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation

Author

Crucitti, L, Crocchiolo, R, Toffalori, C, Mazzi, B, Greco, R, Signori, A, Sizzano, F, Chiesa, L, Zino, E, Lupo Stanghellini, M T, Assanelli, A, Carrabba, M G, Marktel, S, Marcatti, M, Bordignon, C, Corti, C, Bernardi, M, Peccatori, J, Bonini, C, Fleischhauer, K, Ciceri, F, and Vago, L

Published
2015
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28. Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors

Author

Peccatori, J, Forcina, A, Clerici, D, Crocchiolo, R, Vago, L, Stanghellini, M T L, Noviello, M, Messina, C, Crotta, A, Assanelli, A, Marktel, S, Olek, S, Mastaglio, S, Giglio, F, Crucitti, L, Lorusso, A, Guggiari, E, Lunghi, F, Carrabba, M, Tassara, M, Battaglia, M, Ferraro, A, Carbone, M R, Oliveira, G, Roncarolo, M G, Rossini, S, Bernardi, M, Corti, C, Marcatti, M, Patriarca, F, Zecca, M, Locatelli, F, Bordignon, C, Fleischhauer, K, Bondanza, A, Bonini, C, and Ciceri, F

Published
2015
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30. Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors

Author

Styczynski, J., Tridello, G., Koster, L., Iacobelli, S., Biezen, A. van, Werf, S. van der, Mikulska, M., Gil, L., Cordonnier, C., Ljungman, P., Averbuch, D., Cesaro, S., Camara, R. de la, Baldomero, H., Bader, P., Basak, G., Bonini, C., Duarte, R., Dufour, C., Kuball, J., Lankester, A., Montoto, S., Nagler, A., Snowden, J.A., Kroger, N., Mohty, M., Gratwohl, A., Infect Dis Working Party EBMT, UAM. Departamento de Medicina, Styczynski, J., Tridello, G., Koster, L., Iacobelli, S., van Biezen, A., van der Werf, S., Mikulska, M., Gil, L., Cordonnier, C., Ljungman, P., Averbuch, D., Cesaro, S., de la Camara, R., Baldomero, H., Bader, P., Basak, G., Bonini, C., Duarte, R., Dufour, C., Kuball, J., Lankester, A., Montoto, S., Nagler, A., Snowden, J. A., Kroger, N., Mohty, M., and Gratwohl, A.

Subjects
medicine.medical_specialty, Medicina, Epidemiology, medicine.medical_treatment, Hematopoietic stem cell transplantation, Disease, Infections, survival, Communicable Diseases, Article, Cohort Studies, cause of death, Internal medicine, stem cell transplant, medicine, Humans, Haematopoietic stem cell transplantation (HSCT), Risk factor, Cause of death, Transplantation, Leukemia, stem cell transplant, cause of death, survival, business.industry, Incidence (epidemiology), Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Hematology, Settore MED/15, Death, Settore MED/01, surgical procedures, operative, Risk factors, Mycoses, Cohort, business, Cohort study
Abstract

Information on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55′668 deaths in 114′491 patients with HSCT (83.7% allogeneic) for leukemia were investigated in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late). Mortality from all causes decreased from cohort 1 (1980–2001) to cohort 2 (2002–2015) in all post-transplant phases after autologous HSCT. After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type, stem cell source, center, and country- related factors. Their impact varied over the post-transplant phases. Transplant centres have successfully managed to reduce death after HSCT in the early and intermediate post-transplant phases, and have identified risk factors. Late post-transplant care could be improved by focus on groups at risk and better identification of infections of “unknown origin”., The study was funded by the European Group for Blood and Marrow Transplantation EBMT

Published
2019

31. Proceedings From the First International Workshop at Sidra Medicine:'Engineered Immune Cells in Cancer Immunotherapy (EICCI): From Discovery to Off-the-Shelf Development', 15th–16th February 2019, Doha, Qatar

Author

Guerrouahen B., Elnaggar M., Al-Mohannadi A., Kizhakayil D., Bonini C., Benjamin R., Brentjens R., Buchholz C. J., Casorati G., Ferrone S., Locke F. L., Martin F., Schambach A., Turtle C., Veys P., van der Vliet H. J., Maccalli C., Benabdellah K., Bos T., Cugno C., Johnston I., Mohamed A., Ponterio E., Abu Rasheed H. M., Roelands J., Taha R. Y., Guerrouahen, B., Elnaggar, M., Al-Mohannadi, A., Kizhakayil, D., Bonini, C., Benjamin, R., Brentjens, R., Buchholz, C. J., Casorati, G., Ferrone, S., Locke, F. L., Martin, F., Schambach, A., Turtle, C., Veys, P., van der Vliet, H. J., Maccalli, C., Benabdellah, K., Bos, T., Cugno, C., Johnston, I., Mohamed, A., Ponterio, E., Abu Rasheed, H. M., Roelands, J., and Taha, R. Y.

Subjects
lcsh:Immunologic diseases. Allergy, Monoclonal antibody, CAR-T cells, medicine.medical_treatment, T cell, T-Lymphocytes, Immunology, Review, CAR-NK cells, Immunotherapy, Adoptive, Cell therapy, Immune system, Clinical trials, Cancer immunotherapy, Antigen, Neoplasms, medicine, Immunology and Allergy, Animals, Humans, cancer, off-the-shelf development, Qatar, B cell, Cancer, Receptors, Chimeric Antigen, business.industry, clinical trial, Immunotherapy, Monoklonaler Antikörper, TCR engineered lymphocytes, Krebstherapie, CAR-T-Zell-Therapie, monoclonal antibody, immunotherapy, Off-the-shelf development, Tumor antigen, medicine.anatomical_structure, Cancer research, business, Genetic Engineering, lcsh:RC581-607
Abstract

The progress in the isolation and characterization of tumor antigen (TA)-specific T lymphocytes and in the genetic modification of immune cells allowed the clinical development of adoptive cell therapy (ACT). Several clinical studies highlighted the striking clinical activity of T cells engineered to express either Chimeric Antigen (CAR) or T Cell (TCR) Receptors to target molecularly defined antigens expressed on tumor cells. The breakthrough of immunotherapy is represented by the approval of CAR-T cells specific for advanced or refractory CD19+ B cell malignancies by both the Food and Drug Administration (FDA) and the European Medicinal Agency (EMA). Moreover, advances in the manufacturing and gene editing of engineered immune cells contributed to the selection of drug products with desired phenotype, refined specificity and decreased toxicity. An important step toward the optimization of CAR-T cell therapy is the development of “off-the shelf” T cell products that allow to reduce the complexity and the costs of the manufacturing and to render these drugs available for a broad number of cancer patients. The Engineered Immune Cells in Cancer Immunotherapy (EICCI) workshop hosted in Doha, Qatar, renowned experts, from both academia and industry, to present and discuss the progress on both pre-clinical and clinical development of genetically modified immune cells, including advances in the “off-the-shelf” manufacturing. These experts have addressed also organizational needs and hurdles for the clinical grade production and application of these biological drugs., Qatar National Research Fund (QNRF)-Conference Workshop Sponsorship Program CWSP15-W-0911-18001, Associazione Italiana per la Ricerca sul Cancro (AIRC) Ig 18458, Associazione Italiana per la Ricerca sul Cancro (AIRC) 22737, Ministry of Education, Universities and Research (MIUR) PRIN 2017WC8499, Italian Ministry of Health (Research project on CAR T cells for hematological malignancies and solid tumors)

Published
2021

33. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Author

Noviello, M, Manfredi, F, Ruggiero, E, Perini, T, Oliveira, G, Cortesi, F, De Simone, P, Toffalori, C, Gambacorta, V, Greco, R, Peccatori, J, Casucci, M, Casorati, G, Dellabona, P, Onozawa, M, Teshima, T, Griffioen, M, Halkes, C, Falkenburg, J, Stolzel, F, Altmann, H, Bornhauser, M, Waterhouse, M, Zeiser, R, Finke, J, Cieri, N, Bondanza, A, Vago, L, Ciceri, F, Bonini, C, Noviello M., Manfredi F., Ruggiero E., Perini T., Oliveira G., Cortesi F., De Simone P., Toffalori C., Gambacorta V., Greco R., Peccatori J., Casucci M., Casorati G., Dellabona P., Onozawa M., Teshima T., Griffioen M., Halkes C. J. M., Falkenburg J. H. F., Stolzel F., Altmann H., Bornhauser M., Waterhouse M., Zeiser R., Finke J., Cieri N., Bondanza A., Vago L., Ciceri F., Bonini C., Noviello, M, Manfredi, F, Ruggiero, E, Perini, T, Oliveira, G, Cortesi, F, De Simone, P, Toffalori, C, Gambacorta, V, Greco, R, Peccatori, J, Casucci, M, Casorati, G, Dellabona, P, Onozawa, M, Teshima, T, Griffioen, M, Halkes, C, Falkenburg, J, Stolzel, F, Altmann, H, Bornhauser, M, Waterhouse, M, Zeiser, R, Finke, J, Cieri, N, Bondanza, A, Vago, L, Ciceri, F, Bonini, C, Noviello M., Manfredi F., Ruggiero E., Perini T., Oliveira G., Cortesi F., De Simone P., Toffalori C., Gambacorta V., Greco R., Peccatori J., Casucci M., Casorati G., Dellabona P., Onozawa M., Teshima T., Griffioen M., Halkes C. J. M., Falkenburg J. H. F., Stolzel F., Altmann H., Bornhauser M., Waterhouse M., Zeiser R., Finke J., Cieri N., Bondanza A., Vago L., Ciceri F., and Bonini C.

Abstract

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (T SCM ) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1 + Eomes + T-bet − ) BM-T SCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.

Published
2019

35. Beneficial role of CD8+T-cell reconstitution after HLA-haploidentical stem cell transplantation for high-risk acute leukaemias

Author

Bondanza, A., Ruggeri, L., Noviello, M., Eikema, D.J., Bonini, C., Chabannon, C., Werf, S. van der, Biezen, A. van, Wreede, L.C. de, Crucitti, L., Vago, L., Merluzzi, M., Massei, M.S., Veelken, H., Koc, Y., Bader, P., Gruhn, B., Locatelli, F., Ciceri, F., Toubert, A., Velardi, A., Bernardo, M.E., Dazzi, F., Ellard, R., Fleischhauer, K., Greco, R., Hudecek, M., Kohl, U., Kuball, J., Malard, F., Pedrazzoli, P., Rocha, V., Ruggeri, A., Urbano-Ispizua, A., Wang, J.F., Wieten, L., EBMT Cell Therapy Immunobiol Worki, Bondanza, Attilio, Ruggeri, Loredana, Noviello, Maddalena, Eikema, Dirk-Jan, Bonini, Chiara, Chabannon, Christian, van der Werf, Steffie, van Biezen, Anja, de Wreede, Liesbeth C., Crucitti, Lara, Vago, Luca, Merluzzi, Mara, Massei, Maria Speranza, Veelken, Hendrik, Koc, Yener, Bader, Peter, Gruhn, Bernd, Locatelli, Franco, Ciceri, Fabio, Toubert, Antoine, Velardi, Andrea, MUMC+: DA TI Laboratorium (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and MUMC+: DA TI Staf (9)

Subjects
Male, Oncology, BLOOD, COUNT, Medizin, CHILDREN, CD8-Positive T-Lymphocytes, DISEASE, 0302 clinical medicine, Risk Factors, hemic and lymphatic diseases, Cytotoxic T cell, Registries, Child, INDEX, Leukemia, Hematology, Middle Aged, RECOVERY, Haematopoiesis, surgical procedures, operative, medicine.anatomical_structure, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Transplantation, Child, Preschool, 030220 oncology & carcinogenesis, HSCT, Female, Stem cell, Adult, medicine.medical_specialty, Adolescent, T cell, Human leukocyte antigen, Young Adult, 03 medical and health sciences, CD8-positive T-lymphocytes, haematopoietic stem cell transplantation, risk factors, Internal medicine, SCORE, medicine, Humans, IMMUNOTHERAPY, Aged, business.industry, ADULTS, BONE-MARROW-TRANSPLANTATION, Transplantation, Haploidentical, business, CD8, Stem Cell Transplantation, 030215 immunology, RESPONSES
Abstract

HLA-haploidentical haematopoietic stem cell transplantation (haplo-HSCT) is increasingly offered to patients with high-risk acute leukaemia. Unfortunately, haplo-HSCT is followed by a delayed immunoreconstitution. The aim of this EBMT registry study was to explore the clinical impact of lymphocyte subset counts after haplo-HSCT. We considered 144 leukaemic patients transplanted in the period 2001-2012. Pre-transplantation clinical variables and differential immune-cell counts (CD3, CD4, CD8 T cells, NK and B cells) measured before day 100 were evaluated for their capacity to predict overall survival, relapse mortality or non-relapse mortality (NRM). Negative prognostic factors for overall survival were advanced disease state at transplantation, host age and CMV seropositivity. Higher CD3, CD4 and CD8 counts were associated with a better overall survival and a lower NRM. Strikingly, when tested in multivariable analysis, higher CD3 and CD8 counts were still significantly associated with a lower NRM. These results indicate that an accelerated T-cell reconstitution correlates with less transplantation mortality, likely due to the protective role of T cells against viral infections. This observation suggests that CD8+ T-cell counts should be investigated as surrogate biomarkers of outcome in prospective haplo-HSCT trials.

Published
2019

39. Natural killer cell alloreactivity in HLA-haploidentical hematopoietic transplantation: a study on behalf of the CTIWP of the EBMT

Author

Ruggeri, L., Vago, L., Eikema, D. -J., de Wreede, L. C., Ciceri, F., Diaz, M. A., Locatelli, Franco, Jindra, P., Milone, G., Diez-Martin, J. L., Perez-Simon, J. A., Merluzzi, M., Koster, L., van der Werf, S., van Biezen, A., Toubert, A., Nagler, A., Chabannon, C., Bonini, C., Velardi, A., Locatelli F. (ORCID:0000-0002-7976-3654), Ruggeri, L., Vago, L., Eikema, D. -J., de Wreede, L. C., Ciceri, F., Diaz, M. A., Locatelli, Franco, Jindra, P., Milone, G., Diez-Martin, J. L., Perez-Simon, J. A., Merluzzi, M., Koster, L., van der Werf, S., van Biezen, A., Toubert, A., Nagler, A., Chabannon, C., Bonini, C., Velardi, A., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Human leukocyte antigen (HLA) class-I mismatches that trigger donor-versus-recipient natural killer (NK)-cell alloreactivity reduce the incidence of leukemia relapse and improve survival of acute myeloid leukemia patients after T-cell-depleted HLA-haplotype mismatched (“haploidentical”) hematopoietic transplantation. In murine graft-versus-host disease (GvHD) models, alloreactive NK-cells also prevent GvHD. Here we report the results of a non-interventional, prospective study performed on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation. The study was aimed at re-assessing the role of NK-cell alloreactivity in a cohort of haploidentical transplants performed in Europe between 2012 and 2015 and composed of unmanipulated, as well as T-cell-depleted transplants. One hundred thirty-eight patients with acute myeloid or lymphoid leukemias were analyzed. Eighty-six patients received ex-vivo T-cell-depleted transplants, 52 patients received unmanipulated transplants. Fifty patients were transplanted from NK alloreactive donors, 88 from non-NK alloreactive donors. NK cell alloreactivity did not impact on GvHD/relapse-free survival (GRFS) in unmanipulated transplants (HR: 1.66 (0.9–3.1), p = 0.1). In contrast, it did impact beneficially on GRFS in T-cell-depleted transplants (HR: 0.6, (0.3–1.2), p = 0.14, interaction p < 0.001). This effect was the consequence of reduced incidences of acute and chronic GvHD and non-relapse mortality.

Published
2021

44. VENTILATION HETEROGENEITY OF PERIPHERAL AIRWAYS (SACIN*VT) ASSESSED BY NITROGEN MULTIPLE BREATH WASHOUT (N2-MBW) IS AN ACCURATE AND SENSITIVE MARKER OF BRONCHIOLITIS OBLITERANS - THE SAN RAFFAELE EXPERIENCE IN HSCT SETTING: PH-P360

Author

De Giacomi, F., Orsini, A., Guggiari, E., Corti, C., Calcaterra, B., Forcina, A., Perini, T., Piemontese, S., Pavesi, F., Levati, G., Milani, R., Peccatori, J., Bernardi, M., Assanelli, A., Bonini, C., Ciceri, F., Cremona, G., and Lupo-Stanghellini, M.

Published
2014

50. T CELL DEPLETED HAPLOIDENTICAL STEM CELL TRANSPLANTATION FOLLOWED BY ADD-BACKS OF SUICIDE-GENE MODIFIED DONOR T-CELLS OFFERS LONG TERM SURVIVAL FREE OF IMMUNE SUPPRESSION TREATMENT: A 7 YEARS FOLLOW-UP IN 56 PATIENTS: PH-O084

Author

Lupo-Stanghellini, M. T., Greco, R., Oliveira, G., Peccatori, J., Marcatti, M., Guggiari, E., Lunghi, F., Marktel, S., Giglio, F., Bondanza, A., Malerba, A., Trinca, S., Corti, C., Bernardi, M., Lambiase, A., Bordignon, C., Bonini, C., and Ciceri, F.

Published
2014

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