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1. 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

9. T-Cell Replete Haploidentical PBSC Transplantation Using Intensified Myeloablative Conditioning, Post-Transplant Cyclophosphamide and Sirolimus

Author

Greco R, Piemontese S, Cieri N, Giglio F, Morelli M, Messina C, Marcatti M, Marktel S, Carrabba M, Bernardi M, Corti C, Assanelli A, Stanghellini MTL, Bonini C, Vago L, Ciceri F, Peccatori J, Greco, R, Piemontese, S, Cieri, N, Giglio, F, Morelli, M, Messina, C, Marcatti, M, Marktel, S, Carrabba, M, Bernardi, M, Corti, C, Assanelli, A, Stanghellini, Mtl, Bonini, C, Vago, L, Ciceri, F, and Peccatori, J

Published
2016

10. Post-Transplant Cyclophosphamide Eliminates Mature Donor NK Cells Infused with the Graft, Dampening NK Cell Alloreactivity after Haploidentical HSCT

Author

Russo A, Oliveira G, Greco R, Gambacorta V, Cieri N, Toffalori C, Zito L, Piemontese S, Morelli M, Giglio F, Assanelli A, Stanghellini MTL, Bonini C, Peccatori J, Ciceri F, Vago L, Russo, A, Oliveira, G, Greco, R, Gambacorta, V, Cieri, N, Toffalori, C, Zito, L, Piemontese, S, Morelli, M, Giglio, F, Assanelli, A, Stanghellini, Mtl, Bonini, C, Peccatori, J, Ciceri, F, and Vago, L

Published
2016

11. NY-ESO-1 TCR single edited t cells to treat multiple myeloma without inducing GvHD

Author

Mastaglio S, Genovese P, Magnani Z, Landoni E, Camisa B, Schiroli G, Provasi E, Lombardo A, Reik A, Cieri N, Rocchi M, Oliveira G, Escobar G, Casucci M, Gentner B, Spinelli A, Mondino A, Bondanza A, Vago L, Ponzoni M, Ciceri F, Holmes M, Naldini L, Bonini C, Mastaglio, S, Genovese, P, Magnani, Z, Landoni, E, Camisa, B, Schiroli, G, Provasi, E, Lombardo, A, Reik, A, Cieri, N, Rocchi, M, Oliveira, G, Escobar, G, Casucci, M, Gentner, B, Spinelli, A, Mondino, A, Bondanza, A, Vago, L, Ponzoni, M, Ciceri, F, Holmes, M, Naldini, L, and Bonini, C

Published
2016

12. POST-TRANSPLANT CYCLOPHOSPHAMIDE ELIMINATES MATURE DONOR NK CELLS, DAMPENING NATURAL KILLER CELL ALLOREACTIVITY AFTER HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION

Author

Russo A, Oliveira G, Greco R, Gambacorta V, Cieri N, Toffalori C, Zito L, Piemontese S, Morelli M, Giglio F, Assanelli A, Stanghellini MTL, Bonini C, Peccatori J, Ciceri F, Vago L, Russo, A, Oliveira, G, Greco, R, Gambacorta, V, Cieri, N, Toffalori, C, Zito, L, Piemontese, S, Morelli, M, Giglio, F, Assanelli, A, Stanghellini, Mtl, Bonini, C, Peccatori, J, Ciceri, F, and Vago, L

Published
2016

13. Single Chain TCR Gene Editing in Adoptive Cell Therapy for Multiple Myeloma

Author

Mastaglio S, Genovese P, Magnani Z, Landoni E, Camisa B, Schiroli G, Provasi E, Lombardo A, Reik A, Cieri N, Rocchi M, Oliveira G, Escobar G, Casucci M, Gentner B, Spinelli A, Mondino A, Bondanza A, Vago L, Ponzoni M, Ciceri F, Holmes M, Naldini L, Bonini C, Mastaglio, S, Genovese, P, Magnani, Z, Landoni, E, Camisa, B, Schiroli, G, Provasi, E, Lombardo, A, Reik, A, Cieri, N, Rocchi, M, Oliveira, G, Escobar, G, Casucci, M, Gentner, B, Spinelli, A, Mondino, A, Bondanza, A, Vago, L, Ponzoni, M, Ciceri, F, Holmes, M, Naldini, L, and Bonini, C

Published
2016

14. Early recovery of CMV-specific T cells after HLA-haploidentical HSCT with post-transplant cyclophosphamide is associated with a reduced risk of severe infections: a validation study

Author

Noviello M, Greco R, Valtolina V, Forcina A, Pozzato M, Staghellini MTL, Giglio F, Morelli M, Assanelli A, Dalto SC, Piemontese S, Bernardi M, Corti C, Vago L, Cieri N, Peccatori J, Bonini C, Bondanza A, Ciceri F, Noviello, M, Greco, R, Valtolina, V, Forcina, A, Pozzato, M, Staghellini, Mtl, Giglio, F, Morelli, M, Assanelli, A, Dalto, Sc, Piemontese, S, Bernardi, M, Corti, C, Vago, L, Cieri, N, Peccatori, J, Bonini, C, Bondanza, A, and Ciceri, F

Published
2016

15. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: Dynamics and clinical implications

Author

Russo, A, Oliveira, G, Berglund, S, Greco, R, Gambacorta, V, Cieri, N, Toffalori, C, Zito, L, Lorentino, F, Piemontese, S, Morelli, M, Giglio, F, Assanelli, A, Stanghellini, M, Bonini, C, Peccatori, J, Ciceri, F, Luznik, L, Vago, L, Russo, Antonio, Oliveira, Giacomo, Berglund, Sofia, Greco, Raffaella, GAMBACORTA, VALENTINA, Cieri, Nicoletta, Toffalori, Cristina, Zito, Laura, Lorentino, Francesca, Piemontese, Simona, Morelli, Mara, Giglio, Fabio, Assanelli, Andrea, Stanghellini, Maria Teresa Lupo, Bonini, Chiara, Peccatori, Jacopo, Ciceri, Fabio, Luznik, Leo, Vago, Luca, Russo, A, Oliveira, G, Berglund, S, Greco, R, Gambacorta, V, Cieri, N, Toffalori, C, Zito, L, Lorentino, F, Piemontese, S, Morelli, M, Giglio, F, Assanelli, A, Stanghellini, M, Bonini, C, Peccatori, J, Ciceri, F, Luznik, L, Vago, L, Russo, Antonio, Oliveira, Giacomo, Berglund, Sofia, Greco, Raffaella, GAMBACORTA, VALENTINA, Cieri, Nicoletta, Toffalori, Cristina, Zito, Laura, Lorentino, Francesca, Piemontese, Simona, Morelli, Mara, Giglio, Fabio, Assanelli, Andrea, Stanghellini, Maria Teresa Lupo, Bonini, Chiara, Peccatori, Jacopo, Ciceri, Fabio, Luznik, Leo, and Vago, Luca

Abstract

The use of posttransplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis has revolutionized haploidentical hematopoietic stem cell transplantation (HSCT), allowing safe infusion of unmanipulated T cell-replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects natural killer (NK) cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy-based protocols in 2 independent centers. In both series, we documented robust proliferation of donor-derived NK cells immediately after HSCT. After infusion of Cy, a marked reduction of proliferating NK cells was evident, suggesting selective purging of dividing cells. Supporting this hypothesis, proliferating NK cells did not express aldehyde dehydrogenase and were killed by Cy in vitro. After ablation of mature NK cells, starting from day 15 after HSCT and favored by the high levels of interleukin-15 present in patients' sera, immature NK cells (CD62L+NKG2A+KIR-) became highly prevalent, possibly directly stemming from infused hematopoietic stem cells. Importantly, also putatively alloreactive single KIR1 NK cells were eliminated by PT-Cy and were thus decreased in numbers and antileukemic potential at day 30 after HSCT. As a consequence, in an extended series of 99 haplo-HSCT with PT-Cy, we found no significant difference in progression-free survival between patients with or without predicted NK alloreactivity (42% vs 52% at 1 year, P = NS). Our data suggest that the majority of mature NK cells infused with unmanipulated grafts are lost upon PT-Cy administration, blunting NK cell alloreactivity in this transplantation setting

Published
2018

16. Post Transplant Cyclophosphamide (PTCy) and Sirolimus for Haploidentical PBSC HSCT: favorable Immune Reconstitution and Low Rates of GvHD in 40 Patients

Author

Cieri N, Greco R, Crucitti L, Morelli M, Giglio F, Levati G, Assanelli A, Lorentino F, Stanghellini MTL, Vago L, Freitas T, Marktel S, Bernardi M, Corti C, Bonini C, Ciceri F, Peccatori J, Cieri, N, Greco, R, Crucitti, L, Morelli, M, Giglio, F, Levati, G, Assanelli, A, Lorentino, F, Stanghellini, Mtl, Vago, L, Freitas, T, Marktel, S, Bernardi, M, Corti, C, Bonini, C, Ciceri, F, and Peccatori, J

Published
2015

17. Second Haploidentical Hematopoietic Stem Cell Transplantation with Treosulfan-based Conditioning Regimen for Acute Leukemia in Relapse

Author

Peccatori J, Crucitti L, Greco R, Stanghellini MTL, Vago L, Cieri N, Giglio F, Morelli M, Assanelli A, Marcatti M, Carrabba M, Marktel S, Perini T, Lorentino F, Girlanda S, Corti C, Bernardi M, Ciceri F, Peccatori, J, Crucitti, L, Greco, R, Stanghellini, Mtl, Vago, L, Cieri, N, Giglio, F, Morelli, M, Assanelli, A, Marcatti, M, Carrabba, M, Marktel, S, Perini, T, Lorentino, F, Girlanda, S, Corti, C, Bernardi, M, and Ciceri, F

Published
2015

18. Long-term immunological profile of patients treated with haploidentical HSCT and TK-cells to unravel the requirements of memory T cell persistence

Author

Oliveira G, Stanghellini MTL, Cieri N, D'Agostino M, Ruggiero E, Greco R, Mastaglio S, Noviello M, Vago L, Biasco L, Bondanza A, Aiuti A, Lambiase A, Schmidt M, Traversari C, Von Kalle C, Ciceri F, Bordignon C, Bonini C, Oliveira, G, Stanghellini, Mtl, Cieri, N, D'Agostino, M, Ruggiero, E, Greco, R, Mastaglio, S, Noviello, M, Vago, L, Biasco, L, Bondanza, A, Aiuti, A, Lambiase, A, Schmidt, M, Traversari, C, Von Kalle, C, Ciceri, F, Bordignon, C, and Bonini, C

Published
2015

19. LEUKEMIA RELAPSE AFTER ALLOGENENIC HSCT DISPLAYS A DISTINCTIVE IMMUNE-RELATED SIGNATURE, WITH FUNCTIONALLY RELEVANT ALTERATIONS IN HLA CLASS II ANTIGEN PRESENTATION AND T CELL COSTIMULATION

Author

Toffalori C, Riba M, Zito L, Oliveira G, Bucci G, Barcella M, Spinelli O, Crucitti L, Cieri N, Cittaro D, Lazarevic D, Peccatori J, Bernardi M, Bonini C, Rambaldi A, Barlassina C, Stupka E, Bianchi M, Ciceri F, Fleischhauer K, Vago L, Toffalori, C, Riba, M, Zito, L, Oliveira, G, Bucci, G, Barcella, M, Spinelli, O, Crucitti, L, Cieri, N, Cittaro, D, Lazarevic, D, Peccatori, J, Bernardi, M, Bonini, C, Rambaldi, A, Barlassina, C, Stupka, E, Bianchi, M, Ciceri, F, Fleischhauer, K, and Vago, L

Published
2015

20. Erratum: Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory (Science Translational Medicine (2015) 7:319 (319er9))

Author

Oliveira, G., Ruggiero, E., Stanghellini, M. T. L., Cieri, N., D'Agostino, M., Fronza, R., Lulay, C., Dionisio, F., Mastaglio, S., Greco, R., Peccatori, J., Biasco, L., Lambiase, A., Traversari, C., Vago, L., Von Kalle, C., Schmidt, M., AIUTI, ALESSANDRO, AMBROSI, ALESSANDRO, BONDANZA, ATTILIO, BORDIGNON, CLAUDIO, CICERI, FABIO, BONINI, MARIA CHIARA, Oliveira, G., Ruggiero, E., Stanghellini, M. T. L., Cieri, N., D'Agostino, M., Fronza, R., Lulay, C., Dionisio, F., Mastaglio, S., Greco, R., Peccatori, J., Aiuti, Alessandro, Ambrosi, Alessandro, Biasco, L., Bondanza, Attilio, Lambiase, A., Traversari, C., Vago, L., Von Kalle, C., Schmidt, M., Bordignon, Claudio, Ciceri, Fabio, and Bonini, MARIA CHIARA

Subjects
Medicine (all)
Published
2015

21. Tracking genetically engineered lymphocytes long-term reveals the dynamic of T-cell immunological memory

Author

Oliveira G, Ruggiero E, Lupo-Stanghellini MT, Cieri N, D'Agostino M, Fronza R, Biasco L, Dionisio F, Mastaglio S, Greco R, Peccatori J, Aiuti A, Bondanza A, Lambiase A, Traversari C, Vago L, Von Kalle C, Schmidt M, Bordignon C, Ciceri F, Bonini C, Oliveira, G, Ruggiero, E, Lupo-Stanghellini, Mt, Cieri, N, D'Agostino, M, Fronza, R, Biasco, L, Dionisio, F, Mastaglio, S, Greco, R, Peccatori, J, Aiuti, A, Bondanza, A, Lambiase, A, Traversari, C, Vago, L, Von Kalle, C, Schmidt, M, Bordignon, C, Ciceri, F, and Bonini, C

Published
2015

22. Human Herpes Virus 6 Encephalitis: a major challenge after Haploidentical Hematopoietic Stem Cell Transplantation

Author

Greco R, Noviello M, Vago L, Stanghellini MTL, Cieri N, Oliveira G, Giglio F, Morelli M, Valtolina V, Barbanti MC, Lorentino F, Crucitti L, Orsini A, Forcina A, Assanelli A, Carrabba M, Marktel S, Bernardi M, Corti C, Peccatori J, Bordignon C, Bonini C, Ciceri F, Greco, R, Noviello, M, Vago, L, Stanghellini, Mtl, Cieri, N, Oliveira, G, Giglio, F, Morelli, M, Valtolina, V, Barbanti, Mc, Lorentino, F, Crucitti, L, Orsini, A, Forcina, A, Assanelli, A, Carrabba, M, Marktel, S, Bernardi, M, Corti, C, Peccatori, J, Bordignon, C, Bonini, C, and Ciceri, F

Published
2015

23. LEUKEMIA RELAPSES AFTER ALLOGENENIC HSCT DISPLAY A DISTINCTIVE IMMUNE-RELATED SIGNATURE, WITH FUNCTIONALLY RELEVANT ALTERATIONS IN HLA CLASS II ANTIGEN PRESENTATION AND T CELL COSTIMULATION

Author

Toffalori, C., Riba, M., Zito, L., Oliveira, G., Bucci, G., Barcella, M., Spinelli, O., Crucitti, L., Cieri, N., Cittaro, D., Lazarevic, D., Peccatori, J., Bernardi, M., Bonini, C., Rambaldi, A., Barlassina, C., Stupka, E., Bianchi, M., Ciceri, F., Fleischhauer, Katharina, Vago, L., Toffalori, C, Riba, M, Zito, L, Oliveira, G, Bucci, G, Barcella, M, Spinelli, O, Crucitti, L, Cieri, N, Cittaro, D, Lazarevic, D, Peccatori, J, Bernardi, M, Bonini, C, Rambaldi, A, Barlassina, C, Stupka, E, Bianchi, M, Ciceri, F, Fleischhauer, K, and Vago, L

Subjects
Medizin
Published
2015

24. CD3+ graft cell count influence on chronic GVHD in haploidentical allogeneic transplantation using post-transplant cyclophosphamide

Author

Mussetti, A, primary, De Philippis, C, additional, Carniti, C, additional, Bastos-Oreiro, M, additional, Gayoso, J, additional, Cieri, N, additional, Pennisi, M, additional, Ciceri, F, additional, Greco, R, additional, Peccatori, J, additional, Patriarca, F, additional, Mariotti, J, additional, Castagna, L, additional, and Corradini, P, additional

Published
2018
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26. TRACKING T CELL DYNAMICS IN THE FIRST MONTH AFTER ALLOGENEIC HSCT OFFERS A UNIQUE OPPORTUNITY TO UNVEIL THE MECHANISM OF MEMORY STEM T CELL FORMATION IN HUMANS

Author

Cieri, N, Peccatori, J, Oliveira, G, Greco, R, Taccioli, C, Forcato, M, Noviello, M, Valtolina, V, Bondanza, A, Morelli, M, Lunghi, F, Marktel, S, Bellio, L, Bicciato, S, Ciceri, F, Bonini, C, Cieri, N, Peccatori, J, Oliveira, G, Greco, R, Taccioli, C, Forcato, M, Noviello, M, Valtolina, V, Bondanza, A, Morelli, M, Lunghi, F, Marktel, S, Bellio, L, Bicciato, S, Ciceri, F, and Bonini, C

Published
2014

27. LONG-TERM IMMUNOLOGICAL PROFILE AND T CELL DYNAMICS IN PATIENTS TREATED WITH ALLOGENEIC TRANSPLANTATION AND TK-CELLS FOR HEMATOLOGICAL MALIGNANCIES

Author

Oliveira G, Stanghellini MTL, Cieri N, Greco R, D'Agostino M, Noviello M, Valtolina V, Vago L, Bondanza A, Traversari C, Ruggiero E, Paruzynski A, Schmidt M, Von Kalle C, Ciceri F, Bordignon C, Bonini C, Oliveira, G, Stanghellini, Mtl, Cieri, N, Greco, R, D'Agostino, M, Noviello, M, Valtolina, V, Vago, L, Bondanza, A, Traversari, C, Ruggiero, E, Paruzynski, A, Schmidt, M, Von Kalle, C, Ciceri, F, Bordignon, C, and Bonini, C

Published
2014

29. Long-Term Immunological Profile of Patients Treated with Haploidentical HSCT and TK-Cells to Study the Requirements of Memory T Cell Persistence

Author

Oliveira G, Stanghellini MTL, Ruggiero E, Cieri N, D'Agostino M, Greco R, Mastaglio S, Noviello M, Vago L, Biasco L, Bondanza A, Aiuti A, Lambiase A, Schmidt M, Traversari C, von Kalle C, Ciceri F, Bordignon C, Bonini C, Oliveira, G, Stanghellini, Mtl, Ruggiero, E, Cieri, N, D'Agostino, M, Greco, R, Mastaglio, S, Noviello, M, Vago, L, Biasco, L, Bondanza, A, Aiuti, A, Lambiase, A, Schmidt, M, Traversari, C, von Kalle, C, Ciceri, F, Bordignon, C, and Bonini, C

Published
2014

30. Sirolimus and Post Transplant Cyclophosphamide (PT-Cy) Allow the Use of Haploidentical PBSC Grafts Inducing a Favorable Immune Reconstitution with Low Rates of GvHD: Results in 39 Patients

Author

Cieri N, Greco R, Crucitti L, Morelli M, Giglio F, Levati G, Assanelli A, Lorentino F, Stanghellini MTL, Vago L, Freitas T, Marktel S, Bernardi M, Corti C, Bonini C, Ciceri F, Peccatori J, Cieri, N, Greco, R, Crucitti, L, Morelli, M, Giglio, F, Levati, G, Assanelli, A, Lorentino, F, Stanghellini, Mtl, Vago, L, Freitas, T, Marktel, S, Bernardi, M, Corti, C, Bonini, C, Ciceri, F, and Peccatori, J

Published
2014

31. Revealing the Generation of Human Memory Stem T Cells in Haploidentical T-Replete Hematopoietic Stem Cell Transplantation

Author

Cieri N, Oliveira G, Greco R, Forcato M, Taccioli C, Valtolina V, Noviello M, Vago L, Bondanza A, Lunghi F, Marktel S, Bellio L, Bordignon C, Bicciato S, Peccatori J, Ciceri F, Bonini C, Cieri, N, Oliveira, G, Greco, R, Forcato, M, Taccioli, C, Valtolina, V, Noviello, M, Vago, L, Bondanza, A, Lunghi, F, Marktel, S, Bellio, L, Bordignon, C, Bicciato, S, Peccatori, J, Ciceri, F, and Bonini, C

Published
2014

32. Long term persistence of TK-cells and dynamics of memory T cells in patients treated with suicide gene therapy for hematological malignancies

Author

Oliveira G, Stanghellini MTL, Ruggiero E, Cieri N, D'Agostino M, Greco R, Mastaglio S, Noviello M, Vago L, Biasco L, Bondanza A, Aiuti A, Schmidt M, Traversari C, Von Kalle C, Ciceri F, Bordignon C, Bonini C, Oliveira, G, Stanghellini, Mtl, Ruggiero, E, Cieri, N, D'Agostino, M, Greco, R, Mastaglio, S, Noviello, M, Vago, L, Biasco, L, Bondanza, A, Aiuti, A, Schmidt, M, Traversari, C, Von Kalle, C, Ciceri, F, Bordignon, C, and Bonini, C

Published
2014

33. Haploidentical Hematopoietic Stem Cell Transplantation with Treosulfan-Based Conditioning Regimen for Acute Leukemia Relapsing after Initial Allogeneic Transplantation

Author

Peccatori J, Crucitti L, Greco R, Stanghellini MTL, Vago L, Cieri N, Brambilla CZ, Giglio F, Morelli M, Assanelli A, Marcatti M, Carrabba MG, Bonini C, Bernardi M, Ciceri F, Peccatori, J, Crucitti, L, Greco, R, Stanghellini, Mtl, Vago, L, Cieri, N, Brambilla, Cz, Giglio, F, Morelli, M, Assanelli, A, Marcatti, M, Carrabba, Mg, Bonini, C, Bernardi, M, and Ciceri, F

Published
2014

36. Long-Term Immunological Profile and T Cell Dynamics In Patients Treated With Allogeneic Transplantation and TK-Cells For Hematological Malignancies

Author

Oliveira G, Stanghellini MTL, Cieri N, Greco R, Noviello M, Valtolina V, Vago L, Traversari C, Ruggiero E, Paruzynski A, Schmidt M, von Kalle C, Ciceri F, Bordignon C, Bonini C, Oliveira, G, Stanghellini, Mtl, Cieri, N, Greco, R, Noviello, M, Valtolina, V, Vago, L, Traversari, C, Ruggiero, E, Paruzynski, A, Schmidt, M, von Kalle, C, Ciceri, F, Bordignon, C, and Bonini, C

Published
2013

37. Tracking the Fate and Activity of Individual HSC and Memory Stem T Cell Clones in GT Patients through Insertional Tagging

Author

Biasco L, Baricordi C, Cieri N, Bartholomae C, Calabria A, Brigida I, Fronza R, Pellin D, Di Serio C, Montini E, von Kalle C, Schmidt M, Aiuti A., BONINI , MARIA CHIARA, Biasco, L, Baricordi, C, Cieri, N, Bartholomae, C, Calabria, A, Brigida, I, Fronza, R, Pellin, D, Di Serio, C, Montini, E, Bonini, MARIA CHIARA, von Kalle, C, Schmidt, M, and Aiuti, A.

Published
2012

38. Naive-Derived Memory Stem T Cells: A Novel Promising Platform for Cancer Immune-Gene Therapy

Author

Cieri N, Camisa B, Cocchiarella F, Forcato M, Provasi E, Mondino A, Mavilio F, Bicciato S, Recchia A, BONDANZA , ATTILIO, BORDIGNON, CLAUDIO, BONINI , MARIA CHIARA, Cieri, N, Camisa, B, Cocchiarella, F, Forcato, M, Provasi, E, Mondino, A, Bondanza, Attilio, Bordignon, Claudio, Mavilio, F, Bicciato, S, Recchia, A, and Bonini, MARIA CHIARA

Published
2012

39. The importance of be(ginn)ing Naive: implications for cancer immune-gene therapy

Author

Cieri N, Camisa B, Cocchiarella F, Provasi E, Magnani Z, BONDANZA , ATTILIO, Mondino A, Mavilio F, Bicciato S, Recchia A, BONINI , MARIA CHIARA, Cieri, N, Camisa, B, Cocchiarella, F, Provasi, E, Magnani, L, Mondino, A, Bondanza, Attilio, Mavilio, F, Bicciato, S, Recchia, A, Bonini, MARIA CHIARA, and Magnani, Z

Published
2011

43. Early molecular diagnosis of aspergillosis in a patient with acute myeloid leukaemia.

Author

Greco, R., Mancini, N., Peccatori, J., Cieri, N., Vago, L., Giglio, F., Morelli, M., Ghidoli, N., Carletti, S., Levati, G., Crucitti, L., Sala, E., Lupo Stanghellini, M. T., Lorentino, F., Forcina, A., Pavesi, F., Carrabba, M., Marktel, S., Assanelli, A., and Marcatti, M.

Subjects
ASPERGILLOSIS diagnosis, ACUTE myeloid leukemia diagnosis, HISTOLOGY methodology, DIFFERENTIAL diagnosis, MOLECULAR diagnosis, POLYMERASE chain reaction, TOMOGRAPHY, WHITE people, EARLY diagnosis
Published
2014

44. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation

Author

Leo Luznik, Luca Vago, Dietrich W. Beelen, Elisa Montaldo, Matteo Barcella, Robert Zeiser, Bernhard Gentner, Gabriele Bucci, Raynier Devillier, Renato Ostuni, Matteo Carrabba, Masahiro Onozawa, Valentina Gambacorta, Orietta Spinelli, Miguel Waterhouse, Katharina Fleischhauer, Elia Stupka, Ivana Gojo, Chiara Bonini, Cristina Toffalori, Lara Crucitti, Laura Zito, Raffaella Greco, Michela Riba, Matteo Maria Naldini, Dejan Lazarevic, Massimo Bernardi, Maddalena Noviello, Davide Cittaro, Takanori Teshima, Didier Blaise, Jacopo Peccatori, Cristina Barlassina, Francesco Manfredi, Giovanni Tonon, Giacomo Oliveira, Alessandro Rambaldi, Constantijn J.M. Halkes, Marieke Griffioen, Maher Hanoun, Nicoletta Cieri, Fabio Ciceri, Jürgen Finke, Toffalori, C., Zito, L., Gambacorta, V., Riba, M., Oliveira, G., Bucci, G., Barcella, M., Spinelli, O., Greco, R., Crucitti, L., Cieri, N., Noviello, M., Manfredi, F., Montaldo, E., Ostuni, R., Naldini, M. M., Gentner, B., Waterhouse, M., Zeiser, R., Finke, J., Hanoun, M., Beelen, D. W., Gojo, I., Luznik, L., Onozawa, M., Teshima, T., Devillier, R., Blaise, D., Halkes, C. J. M., Griffioen, M., Carrabba, M. G., Bernardi, M., Peccatori, J., Barlassina, C., Stupka, E., Lazarevic, D., Tonon, G., Rambaldi, A., Cittaro, D., Bonini, C., Fleischhauer, K., Ciceri, F., Vago, L., Toffalori, C, Zito, L, Gambacorta, V, Riba, M, Oliveira, G, Bucci, G, Barcella, M, Spinelli, O, Greco, R, Crucitti, L, Cieri, N, Noviello, M, Manfredi, F, Montaldo, E, Ostuni, R, Naldini, M, Gentner, B, Waterhouse, M, Zeiser, R, Finke, J, Hanoun, M, Beelen, D, Gojo, I, Luznik, L, Onozawa, M, Teshima, T, Devillier, R, Blaise, D, Halkes, C, Griffioen, M, Carrabba, M, Bernardi, M, Peccatori, J, Barlassina, C, Stupka, E, Lazarevic, D, Tonon, G, Rambaldi, A, Cittaro, D, Bonini, C, Fleischhauer, K, Ciceri, F, and Vago, L

Subjects
0301 basic medicine, Myeloid, medicine.medical_treatment, Antigen presentation, Medizin, Reproducibility of Result, Hematopoietic stem cell transplantation, Lymphocyte Activation, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, medicine, Humans, Transplantation, Homologous, RNA, Messenger, Transplantation, Homologou, business.industry, Gene Expression Regulation, Leukemic, Gene Expression Profiling, Histocompatibility Antigens Class II, Hematopoietic Stem Cell Transplantation, Reproducibility of Results, Myeloid leukemia, General Medicine, medicine.disease, Transplantation, Haematopoiesis, Leukemia, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, business, CD80, Human
Abstract

Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-gamma or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.

Published
2019

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

Author

Masahiro Onozawa, Francesco Manfredi, Marieke Griffioen, Filippo Cortesi, Martin Bornhäuser, Luca Vago, Valentina Gambacorta, Chiara Bonini, Cristina Toffalori, Monica Casucci, Jhf Falkenburg, Raffaella Greco, Giacomo Oliveira, Tommaso Perini, Miguel Waterhouse, Maddalena Noviello, Fabio Ciceri, Jürgen Finke, Takanori Teshima, Constantijn J.M. Halkes, Robert Zeiser, Paolo Dellabona, Giulia Casorati, Pantaleo De Simone, Eliana Ruggiero, Heidi Altmann, Friedrich Stölzel, Attilio Bondanza, Nicoletta Cieri, Jacopo Peccatori, 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, and Bonini, C

Subjects
0301 basic medicine, Male, Myeloid, T-Lymphocytes, medicine.medical_treatment, Programmed Cell Death 1 Receptor, General Physics and Astronomy, 02 engineering and technology, Hematopoietic stem cell transplantation, Antineoplastic Agent, Receptors, KIR, Recurrence, Retrospective Studie, hemic and lymphatic diseases, CTLA-4 Antigen, lcsh:Science, Hepatitis A Virus Cellular Receptor 2, Transplantation, Homologou, Multidisciplinary, Clonal anergy, Gene Expression Regulation, Leukemic, Remission Induction, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Middle Aged, 021001 nanoscience & nanotechnology, Lymphocyte Activation Gene 3 Protein, 3. Good health, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Bone Marrow Cell, Female, 0210 nano-technology, Human, Signal Transduction, Adult, T cell, Science, Antineoplastic Agents, Bone Marrow Cells, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Antigens, CD, Signaling Lymphocytic Activation Molecule Family, Glucocorticoid-Induced TNFR-Related Protein, medicine, Humans, Transplantation, Homologous, Retrospective Studies, Clonal Anergy, business.industry, General Chemistry, medicine.disease, Transplantation, 030104 developmental biology, T-Lymphocyte, Immunology, lcsh:Q, Bone marrow, business, Immunologic Memory
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 (TSCM) 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-TSCM 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., Allogeneic hematopoietic cell transplantation is the standard treatment of acute myeloid leukemia, but many patients relapse. Here the authors show increased markers of exhaustion and cancer antigen specificity within bone marrow-residing memory T cells precede and potentially predict the relapse.

Published
2019
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46. CD4+ Memory Stem T Cells Recognizing Citrullinated Epitopes Are Expanded in Patients With Rheumatoid Arthritis and Sensitive to Tumor Necrosis Factor Blockade

Author

Chiara Bonini, M. Tassara, Angelo A. Manfredi, Beatrice Claudia Cianciotti, Elena Baldissera, Zulma Magnani, Eliana Ruggiero, Fabio Ciceri, Corrado Campochiaro, Mattia Baldini, Nicoletta Cieri, Giacomo Oliveira, Matteo Doglio, Cianciotti, B. C., Ruggiero, E., Campochiaro, C., Oliveira, G., Magnani, Z. I., Baldini, M., Doglio, M., Tassara, M., Manfredi, A. A., Baldissera, E., Ciceri, F., Cieri, N., and Bonini, C.

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, T cell, Immunology, Cell, Epitopes, T-Lymphocyte, Arthritis, Biology, Epitope, Flow cytometry, Arthritis, Rheumatoid, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, medicine, Humans, Immunology and Allergy, Aged, medicine.diagnostic_test, T-cell receptor, Middle Aged, Cell sorting, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Antirheumatic Agents, 030220 oncology & carcinogenesis, Female, Tumor Necrosis Factor Inhibitors, Tumor necrosis factor alpha, Immunologic Memory
Abstract

Objective Memory stem T (Tscm) cells are long-lived, self-renewing T cells that play a relevant role in immunologic memory. This study was undertaken to investigate whether Tscm cells accumulate in rheumatoid arthritis (RA). Methods The polarization and differentiation profiles of circulating T cells were assessed by flow cytometry. Antigen-specific T cells were characterized by staining with major histocompatibility complex class II tetramers. The T cell receptor (TCR) repertoire was analyzed by high-throughput sequencing using an unbiased RNA-based approach in CD4+ T cell subpopulations sorted by fluorescence-activated cell sorting. Results We analyzed the dynamics of circulating Tscm cells (identified as CD45RA+CD62L+CD95+ T cells) by flow cytometry in 27 RA patients, 16 of whom were also studied during treatment with the anti-tumor necrosis factor (anti-TNF) agent etanercept. Age-matched healthy donors were used as controls. CD4+ Tscm cells were selectively and significantly expanded in RA patients in terms of frequency and absolute numbers, and significantly contracted upon anti-TNF treatment. Expanded CD4+ Tscm cells displayed a prevalent Th17 phenotype and a skewed TCR repertoire in RA patients, with the 10 most abundant clones representing up to 53.7% of the detected sequences. CD4+ lymphocytes specific for a citrullinated vimentin (Cit-vimentin) epitope were expanded in RA patients with active disease. Tscm cells accounted for a large fraction of Cit-vimentin-specific CD4+ cells. Conclusion Our results indicate that Tscm cells, including expanded clones specific for relevant autoantigens, accumulate in RA patients not exposed to biologic agents, and might be involved in the natural history of the disease. Further analysis of Tscm cell dynamics in autoimmune disorders may have implications for the design and efficacy assessment of innovative therapies.

Published
2020
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47. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: Dynamics and clinical implications

Author

Maria Teresa Lupo Stanghellini, Raffaella Greco, Sofia Berglund, Leo Luznik, Francesca Lorentino, Giacomo Oliveira, Fabio Giglio, Andrea Assanelli, Mara Morelli, Valentina Gambacorta, Simona Piemontese, Jacopo Peccatori, Antonio Russo, Luca Vago, Nicoletta Cieri, Fabio Ciceri, Chiara Bonini, Cristina Toffalori, Laura Zito, Russo, Antonio, Oliveira, Giacomo, Berglund, Sofia, Greco, Raffaella, Gambacorta, Valentina, Cieri, Nicoletta, Toffalori, Cristina, Zito, Laura, Lorentino, Francesca, Piemontese, Simona, Morelli, Mara, Giglio, Fabio, Assanelli, Andrea, Stanghellini, Maria Teresa Lupo, Bonini, Chiara, Peccatori, Jacopo, Ciceri, Fabio, Luznik, Leo, Vago, Luca, Russo, A, Oliveira, G, Berglund, S, Greco, R, Gambacorta, V, Cieri, N, Toffalori, C, Zito, L, Lorentino, F, Piemontese, S, Morelli, M, Giglio, F, Assanelli, A, Stanghellini, M, Bonini, C, Peccatori, J, Ciceri, F, Luznik, L, and Vago, L

Subjects
medicine.medical_specialty, Cyclophosphamide, medicine.medical_treatment, Cell, Immunology, Hematopoietic stem cell transplantation, Biology, Biochemistry, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, Internal medicine, medicine, Transplantation, Hematology, Hematopoietic Stem Cell Transplantation, Cell Biology, Killer Cells, Natural, Haematopoiesis, surgical procedures, operative, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Stem cell, 030215 immunology, medicine.drug
Abstract

The use of posttransplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis has revolutionized haploidentical hematopoietic stem cell transplantation (HSCT), allowing safe infusion of unmanipulated T cell-replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects natural killer (NK) cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy-based protocols in 2 independent centers. In both series, we documented robust proliferation of donor-derived NK cells immediately after HSCT. After infusion of Cy, a marked reduction of proliferating NK cells was evident, suggesting selective purging of dividing cells. Supporting this hypothesis, proliferating NK cells did not express aldehyde dehydrogenase and were killed by Cy in vitro. After ablation of mature NK cells, starting from day 15 after HSCT and favored by the high levels of interleukin-15 present in patients' sera, immature NK cells (CD62L+NKG2A+KIR-) became highly prevalent, possibly directly stemming from infused hematopoietic stem cells. Importantly, also putatively alloreactive single KIR+ NK cells were eliminated by PT-Cy and were thus decreased in numbers and antileukemic potential at day 30 after HSCT. As a consequence, in an extended series of 99 haplo-HSCT with PT-Cy, we found no significant difference in progression-free survival between patients with or without predicted NK alloreactivity (42% vs 52% at 1 year, P = NS). Our data suggest that the majority of mature NK cells infused with unmanipulated grafts are lost upon PT-Cy administration, blunting NK cell alloreactivity in this transplantation setting.

Published
2018

48. CD3+ graft cell count influence on chronic GVHD in haploidentical allogeneic transplantation using post-transplant cyclophosphamide

Author

Raffaella Greco, C. Carniti, Francesca Patriarca, C. De Philippis, Fabio Ciceri, Nicoletta Cieri, Jacopo Peccatori, Alberto Mussetti, Martina Pennisi, Mariana Bastos-Oreiro, Jorge Gayoso, Paolo Corradini, L. Castagna, Jacopo Mariotti, Mussetti, A., De Philippis, C., Carniti, C., Bastos-Oreiro, M., Gayoso, J., Cieri, N., Pennisi, M., Ciceri, F., Greco, R., Peccatori, J., Patriarca, F., Mariotti, J., Castagna, L., and Corradini, P.

Subjects
Adult, Male, medicine.medical_specialty, Allogeneic transplantation, Cyclophosphamide, CD3 Complex, CD34, Graft vs Host Disease, Gastroenterology, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Transplantation, Homologous, Aged, Transplantation, business.industry, Incidence (epidemiology), Graft Survival, Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Hematology, Middle Aged, surgical procedures, operative, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Chronic Disease, Transplantation, Haploidentical, Female, Bone marrow, business, 030215 immunology, Cohort study, medicine.drug
Abstract

The effects of graft or donor characteristics in haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PT-Cy) are largely unknown. In this multicenter retrospective study we analyzed the correlations between graft cell composition (CD34+, CD3+) and donor features on transplant outcomes in 234 patients who underwent HCT between 2010 and 2016. On multivariate analysis, the use of peripheral blood stem cells (PBSC) was associated with an increased incidence of grade 2–4 acute GVHD [HR 1.94, 95% confidence Interval (CI) = 1.01–3.98, p = 0.05]. An elevated CD3+ graft content was associated with an increased incidence of all-grade chronic GVHD [HR 1.36 (95% CI = 1.06–1.74), p = 0.01]. This effect was confirmed only for the PBSC graft group. A higher CD34+ graft content had a protective role on non-relapse mortality [HR 0.78 (95% CI = 0.62–0.96), p = 0.02] but this was confirmed only for the bone marrow (BM)-derived graft cohort. Donor characteristics did not influence any outcomes. GVHD prophylaxis should be modulated accordingly to CD3+ graft content, especially when a PBSC graft is used. These results need further validation in prospective trials.

Published
2017

49. Low-dose antithymocyte globulin, post-transplant cyclophosphamide and sirolimus as graft-versus-host disease prophylaxis in unrelated donor transplants

Author

Maria Chiara Barbanti, Fabio Giglio, Matteo Carrabba, Maria Teresa Lupo Stanghellini, Carlo Messina, Raffaella Greco, Chiara Bonini, Jacopo Peccatori, Mara Morelli, Sarah Marktel, Raffaella Milani, Magda Marcatti, Nicoletta Cieri, Consuelo Corti, Lara Crucitti, Massimo Bernardi, Tommaso Perini, Luca Vago, Elisa Sala, Simona Piemontese, Francesca Pavesi, Fabio Ciceri, Andrea Assanelli, Greco, R, Crucitti, L, Vago, L, Cieri, N, Giglio, F, Stanghellini, Mtl, Morelli, M, Barbanti, Mc, Piemontese, S, Perini, T, Sala, E, Pavesi, F, Messina, C, Milani, R, Marcatti, M, Marktel, S, Carrabba, M, Bernardi, M, Corti, C, Assanelli, A, Bonini, C, Ciceri, F, Peccatori, J, and Carrabba, Mg

Subjects
medicine.medical_specialty, Globulin, biology, business.industry, Immunology, Congenital cytomegalovirus infection, Cell Biology, Hematology, medicine.disease_cause, medicine.disease, Biochemistry, Gastroenterology, BK virus, Transplantation, surgical procedures, operative, Graft-versus-host disease, Internal medicine, Sirolimus, medicine, biology.protein, Rituximab, business, medicine.drug, Hemorrhagic cystitis
Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only cure for several patients with high-risk hematological malignancies. Recent advances in supportive therapies have significantly reduced the treatment-related mortality over the last decades. Nevertheless graft-versus-host disease (GvHD) still represents a major complication, and research is needed to achieve further progress in this area of transplantation. Moreover, although initial studies suggested relative equivalence, recent and large prospective studies showed higher rates of acute and chronic GvHD, and worse survival in allo-HSCT from unrelated donors (URD) compared with HLA-identical sibling donors. Following our encouraging results in haplodentical setting with the more recently post-transplantation cyclophosphamide (PTCy) and sirolimus as GvHD prophylaxis (Cieri et al, 2015), in this study we investigated whether the incorporation of low dose anti-thymocyte globulin (ATG) to PTCy and sirolimus GvHD prophylactic approach, may alleviate some of the increased alloreactivity associated with URD transplants. We retrospectively evaluated a cohort of 21 haematological patients receiving URD allo-HSCT in the San Raffaele Haematology and BMT Unit, from 2013 to 2015. All subjects had high-risk hematologic malignancies, with the most common diagnosis being myeloid diseases (52%). A total of 11 patients had active disease at HSCT, while 9 were in hematologic remission. Nine patients scored high according to disease risk index defined by Armand et al, 10 scored intermediate, while only 2 had a low disease score. Myeloablative conditioning consisted of treosulfan (14 g/m2/day) on days -6 to -4, fludarabine (30 mg/m2/day) on days -6 to -2, and melphalan (70 mg/m2/day) on days -2 and -1, followed by T-replete G-CSF-mobilized PBSCs (n=19) or BM grafts (n=2). Whether 12 patients received stem cells from HLA- matched URD (fully 10/10 HLA matched), the remaining 9 had one-locus HLA-mismatched from their donors. During conditioning patients received ATG-Fresenius 5 mg/kg per day IV on day -4 to -2. In vivo B-cell depletion was obtained by rituximab (i.v. 375mg/m2 given as a single dose on day -1). Postgrafting immunosuppression consisted of PTCy (50 mg/kg/day) on days 3 and 4. Sirolimus was given orally from day 5, and monitored to maintain a target therapeutic plasma level of 5-14 ng/ml. According to chimeric status and evidence of GVHD, the dosage of sirolimus was tapered during the second month post-transplantation, ending in complete withdrawal within the sixth month after HSCT. Mycophenolate mofetil (MMF) was initiated orally at 10 mg/kg t.i.d. on day 5 after HSCT, and withdrawn on day 30. Median follow up was 247 days (range 29-486) from HSCT. All patients were engrafted in a median time of 17 days (range, 14-51 days), with full donor chimerism achieved by day 30. Poor graft function was observed in 11 patients. Post-HSCT recovery of lymphocyte subsets was lengthy as compared to other unmanipulated HSCT, with a median time to CD3>100/ml of 41 days (range, 22-389 days) by flow-cytometry, while 5 patients never reached immune reconstitution. All except one developed febrile neutropenia during aplasia. We observed a high rate of serious infections: severe pneumonia in 7 cases (5 required NIV, 4 were admitted to ICU), CMV reactivation in 13 (3 CMV disease), HHV6 reactivation in 10, BK virus haemorrhagic cystitis in 2 patients. Although the overall mortality associated with these complications was limited, as evidenced by a favourable NRM, it caused significant morbidity in patients and often required aggressive therapies, potentially contributing to poor graft function. The incidences of acute and chronic GVHD were low. A grade II-IV acute GvHD was reported in 10% patients, while five patients developed chronic GvHD (mild in 4 cases, only one moderate). Non-relapse mortality (NRM) at 100 days and 1 year was 4.8% and 20.7%, respectively. The estimated 1-year overall survival (OS) and relapse incidence were 51% and 22.5% respectively. Although limited by a small number of patients with relatively short follow-up, our study suggests that URD allo-HSCT with ATG, PTCy and sirolimus-based GvHD prophylaxis, can be very effective in preventing GvHD, but at the expense of delayed immune reconstitution and high rate of infectious complications, while warranting acceptable NRM and relapse incidence. Disclosures Bonini: MolMed S.p.A: Consultancy.

Published
2016

50. Improving the safety of cell therapy with the TK-suicide gene

Author

Raffaella eGreco, Giacomo eOliveira, Maria Teresa eLupo Stanghellini, Luca eVago, Attilio eBondanza, Jacopo ePeccatori, Nicoletta eCieri, Sarah eMarktel, Sara eMastaglio, Claudio eBordignon, Chiara eBonini, Fabio eCiceri, Greco, R, Oliveira, G, Lupo Stanghellini, Mt, Vago, L, Bondanza, Attilio, Peccatori, J, Cieri, N, Marktel, S, Mastaglio, S, Bordignon, Claudio, Bonini, MARIA CHIARA, and Ciceri, Fabio

Subjects
Ganciclovir, Genetic enhancement, TK-suicide gene, Review, suicide gene therapy, Cell therapy, Immune system, cellular adoptive immunotherapy, medicine, Pharmacology (medical), allogeneic hematopoietic stem cell transplantation, Pharmacology, business.industry, lcsh:RM1-950, Gene Therapy, Suicide gene, Donor Lymphocytes, Allogeneic haematopoietic stem cell transplantation, Transplantation, surgical procedures, operative, lcsh:Therapeutics. Pharmacology, TK cells, Immunology, Stem cell, cell therapy, business, medicine.drug
Abstract

While opening new frontiers for the cure of malignant and non-malignant diseases, the increasing use of cell therapy poses also several new challenges related to the safety of a living drug. The most effective and consolidated cell therapy approach is allogeneic haematopoietic stem cell transplantation (HSCT), the only cure for several patients with high-risk haematological malignancies. The potential of allogeneic HSCT is strictly dependent on the donor immune system, particularly on alloreactive T lymphocytes, that promote the beneficial graft-versus-tumour effect (GvT), but may also trigger the detrimental graft-versus-host-disease (GvHD). Gene transfer technologies allow to manipulate donor T cells to enforce GvT and foster immune reconstitution, while avoiding or controlling GvHD. The suicide gene approach is based on the transfer of a suicide gene into donor lymphocytes, for a safe infusion of a wide T cell repertoire, that might be selectively controlled in vivo in case of GvHD. The herpes simplex virus thymidine kinase (HSV-TK) is the suicide gene most extensively tested in humans. Expression of HSV-TK in donor lymphocytes confers lethal sensitivity to the anti-herpes drug, ganciclovir. Progressive improvements in suicide genes, vector technology and transduction protocols have allowed to overcome the toxicity of GvHD while preserving the antitumor efficacy of allogeneic HSCT. Several phase I-II clinical trials in the last 20 years document the safety and the efficacy of HSV-TK approach, able to maintain its clear value over the last decades, in the rapidly progressing horizon of cancer cellular therapy.

Published
2015
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