62 results on '"Bertaina, V."'
Search Results
2. Achievement of operational tolerance in a pediatric liver transplant recipient following successful hematopoietic stem cell transplantation from a different donor
- Author
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Algeri, M., Velardi, E., Spada, M., Galaverna, F., Carta, R., Vinti, L., Palumbo, G., Gaspari, S., Pietrobattista, A., Boccieri, E., Becilli, M., Francalanci, P., Bertaina, V., Merli, P., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Algeri, M., Velardi, E., Spada, M., Galaverna, F., Carta, R., Vinti, L., Palumbo, G., Gaspari, S., Pietrobattista, A., Boccieri, E., Becilli, M., Francalanci, P., Bertaina, V., Merli, P., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Hematopoietic stem cell transplantation (HSCT)–based approaches are increasingly investigated strategies to induce tolerance in recipients of solid allografts. However, in the majority of cases, these approaches rely on the infusion of hematopoietic stem cells recovered from the same solid organ donor. In this report, we describe the case of a boy who received liver transplantation from a deceased donor, who had successfully underwent allogeneic HSCT from an unrelated donor for hepatitis-associated aplastic anemia. In this patient, it was possible to permanently withdraw post-HSCT immune suppression without causing any sign of liver graft dysfunction. To the best of our knowledge, this is the first case of operational tolerance documented in a patient who received combined liver transplantation and HSCT from different donors.
- Published
- 2023
3. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma
- Author
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Del Bufalo, F., De Angelis, B., Caruana, I., Del Baldo, G., De Ioris, M. A., Serra, A., Mastronuzzi, A., Cefalo, M. G., Pagliara, D., Amicucci, M., Li Pira, G., Leone, G., Bertaina, V., Sinibaldi, M., Di Cecca, S., Guercio, M., Abbaszadeh, Z., Iaffaldano, L., Gunetti, M., Iacovelli, S., Bugianesi, R., Macchia, S., Algeri, M., Merli, P., Galaverna, F., Abbas, R., Garganese, M. C., Villani, M. F., Colafati, G. S., Bonetti, F., Rabusin, M., Perruccio, K., Folsi, V., Quintarelli, C., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Del Bufalo, F., De Angelis, B., Caruana, I., Del Baldo, G., De Ioris, M. A., Serra, A., Mastronuzzi, A., Cefalo, M. G., Pagliara, D., Amicucci, M., Li Pira, G., Leone, G., Bertaina, V., Sinibaldi, M., Di Cecca, S., Guercio, M., Abbaszadeh, Z., Iaffaldano, L., Gunetti, M., Iacovelli, S., Bugianesi, R., Macchia, S., Algeri, M., Merli, P., Galaverna, F., Abbas, R., Garganese, M. C., Villani, M. F., Colafati, G. S., Bonetti, F., Rabusin, M., Perruccio, K., Folsi, V., Quintarelli, C., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma. Methods: In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01). Results: A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×106 CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×106 CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively. Conclusions: The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others
- Published
- 2023
4. Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL
- Author
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del Bufalo, F., Becilli, M., Rosignoli, C., De Angelis, B., Algeri, M., Hanssens, L., Gunetti, M., Iacovelli, S., Li Pira, G., Girolami, E., Leone, G., Lazzaro, S., Bertaina, V., Sinibaldi, M., Di Cecca, S., Iaffaldano, L., Kunkele, A., Boccieri, E., Del Baldo, G., Pagliara, D., Merli, P., Carta, R., Quintarelli, C., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), del Bufalo, F., Becilli, M., Rosignoli, C., De Angelis, B., Algeri, M., Hanssens, L., Gunetti, M., Iacovelli, S., Li Pira, G., Girolami, E., Leone, G., Lazzaro, S., Bertaina, V., Sinibaldi, M., Di Cecca, S., Iaffaldano, L., Kunkele, A., Boccieri, E., Del Baldo, G., Pagliara, D., Merli, P., Carta, R., Quintarelli, C., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or displaying profound lymphopenia and/or rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T cells transduced with a second-generation (4.1BB) CD19-directed CAR for treatment of patients with BCP-ALL in a hospital-exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR–Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy-based manufacturing process (CD19-CAR–Lenti_ALLO). Thirteen children/young adults received ALLO–CAR-T cells between March 2021 and October 2022. Doses ranged between 1.0 × 106 and 3.0 × 106 CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell–associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO–CAR-T cells from an HLA-haploidentical donor, experienced GVHD. Two patients received ALLO–CAR-T cells before HSCT and showed a significant expansion of CAR-T cells without any sign of GVHD. All patients obtained complete remission (CR) with absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells.
- Published
- 2023
5. Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts
- Author
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Quintarelli, C, Guercio, M, Manni, S, Boffa, I, Sinibaldi, M, DI Cecca, S, Caruso, S, Abbaszadeh, Z, Camera, A, Cembrola, B, Ciccone, R, Orfao, A, Martin-Martin, L, Gutierrez-Herrero, S, Herrero-Garcia, M, Cazzaniga, G, Nunes, V, Songia, S, Marcatili, P, Marin, F, Ruella, M, Bertaina, V, Vinti, L, Del Bufalo, F, Algeri, M, Merli, P, De Angelis, B, Locatelli, F, Quintarelli C., Guercio M., Manni S., Boffa I., Sinibaldi M., DI Cecca S., Caruso S., Abbaszadeh Z., Camera A., Cembrola B., Ciccone R., Orfao A., Martin-Martin L., Gutierrez-Herrero S., Herrero-Garcia M., Cazzaniga G., Nunes V., Songia S., Marcatili P., Marin F. I., Ruella M., Bertaina V., Vinti L., Del Bufalo F., Algeri M., Merli P., De Angelis B., Locatelli F., Quintarelli, C, Guercio, M, Manni, S, Boffa, I, Sinibaldi, M, DI Cecca, S, Caruso, S, Abbaszadeh, Z, Camera, A, Cembrola, B, Ciccone, R, Orfao, A, Martin-Martin, L, Gutierrez-Herrero, S, Herrero-Garcia, M, Cazzaniga, G, Nunes, V, Songia, S, Marcatili, P, Marin, F, Ruella, M, Bertaina, V, Vinti, L, Del Bufalo, F, Algeri, M, Merli, P, De Angelis, B, Locatelli, F, Quintarelli C., Guercio M., Manni S., Boffa I., Sinibaldi M., DI Cecca S., Caruso S., Abbaszadeh Z., Camera A., Cembrola B., Ciccone R., Orfao A., Martin-Martin L., Gutierrez-Herrero S., Herrero-Garcia M., Cazzaniga G., Nunes V., Songia S., Marcatili P., Marin F. I., Ruella M., Bertaina V., Vinti L., Del Bufalo F., Algeri M., Merli P., De Angelis B., and Locatelli F.
- Abstract
Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells. BackgroundMethods We evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing. Results The presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells. Conclusions Taken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts.
- Published
- 2021
6. TCRab/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different non malignant disorders
- Author
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Merli, P., Pagliara, D., Galaverna, F., Pira, G. L., Andreani, M., Leone, G., Amodio, D., Pinto, R. M., Bertaina, A., Bertaina, V., Mastronuzzi, A., Strocchio, L., Boccieri, E., Pende, D., Falco, M., Nardo, M. D., Del Bufalo, F., Algeri, M., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Merli, P., Pagliara, D., Galaverna, F., Pira, G. L., Andreani, M., Leone, G., Amodio, D., Pinto, R. M., Bertaina, A., Bertaina, V., Mastronuzzi, A., Strocchio, L., Boccieri, E., Pende, D., Falco, M., Nardo, M. D., Del Bufalo, F., Algeri, M., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Several nonmalignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders, or metabolic diseases, lacking a fully matched donor or requiring urgent transplantation underwent TCRab/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study. The median age at transplant was 3.5 years (range 0.3-16.1); the median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (eg, aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/ recent infections at the time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade 1-2 acute GVHD was 14.4% (no patient developed grade 3-4 acute GVHD). Only one patient at risk developed mild chronic GVHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRab/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment of children with NMDs. Prompt donor availability, low incidence of GVHD, and TRM make this strategy an attractive option in NMDs patients. The study is registered at ClinicalTrial.gov as NCT01810120.
- Published
- 2022
7. HLA-haploidentical TCRab1/CD191-depleted stem cell transplantation in children and young adults with Fanconi anemia
- Author
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Strocchio, L., Pagliara, D., Algeri, M., Pira, G. L., Rossi, F., Bertaina, V., Leone, G., Pinto, R. M., Andreani, M., Agolini, E., Girardi, K., Gaspari, S., Grapulin, L., Bufalo, F. D., Novelli, A., Merli, P., and Locatelli, Franco
- Subjects
HLA-haploidentical tranpslant ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA - Published
- 2021
8. Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts
- Author
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Quintarelli, C., Guercio, M., Manni, S., Boffa, I., Sinibaldi, M., DI Cecca, S., Caruso, S., Abbaszadeh, Z., Camera, A., Cembrola, B., Ciccone, R., Orfao, A., Martin-Martin, L., Gutierrez-Herrero, S., Herrero-Garcia, M., Cazzaniga, G., Nunes, V., Songia, S., Marcatili, P., Marin, F. I., Ruella, M., Bertaina, V., Vinti, L., Del Bufalo, F., Algeri, M., Merli, P., De Angelis, B., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Quintarelli, C., Guercio, M., Manni, S., Boffa, I., Sinibaldi, M., DI Cecca, S., Caruso, S., Abbaszadeh, Z., Camera, A., Cembrola, B., Ciccone, R., Orfao, A., Martin-Martin, L., Gutierrez-Herrero, S., Herrero-Garcia, M., Cazzaniga, G., Nunes, V., Songia, S., Marcatili, P., Marin, F. I., Ruella, M., Bertaina, V., Vinti, L., Del Bufalo, F., Algeri, M., Merli, P., De Angelis, B., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells. BackgroundMethods We evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing. Results The presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells. Conclusions Taken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts.
- Published
- 2021
9. Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma
- Author
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Tumino, N., Weber, G., Besi, F., Del Bufalo, F., Bertaina, V., Paci, P., Quatrini, L., Antonucci, L., Sinibaldi, M., Quintarelli, C., Maggi, E., De Angelis, B., Locatelli, Franco, Moretta, L., Vacca, P., Caruana, I., Locatelli F. (ORCID:0000-0002-7976-3654), Tumino, N., Weber, G., Besi, F., Del Bufalo, F., Bertaina, V., Paci, P., Quatrini, L., Antonucci, L., Sinibaldi, M., Quintarelli, C., Maggi, E., De Angelis, B., Locatelli, Franco, Moretta, L., Vacca, P., Caruana, I., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
The outcome of patients affected by high-risk or metastatic neuroblastoma (NB) remains grim, with ≥ 50% of the children experiencing relapse or progression of the disease despite multimodal, intensive treatment. In order to identify new strategies to improve the overall survival and the quality of life of these children, we recently developed and optimized a third-generation GD2-specific chimeric antigen receptor (CAR) construct, which is currently under evaluation in our Institution in a phase I/II clinical trial (NCT03373097) enrolling patients with relapsed/refractory NB. We observed that our CAR T-cells are able to induce marked tumor reduction and even achieve complete remission with a higher efficiency than that of other CAR T-cells reported in previous studies. However, often responses are not sustained and relapses occur. Here, we demonstrate for the first time a mechanism of resistance to GD2.CAR T-cell treatment, showing how polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) increase in the peripheral blood (PB) of NB patients after GD2.CAR T-cell treatment in case of relapse and loss of response. In vitro, isolated PMN-MDSC demonstrate to inhibit the anti-tumor cytotoxicity of different generations of GD2.CAR T-cells. Gene-expression profiling of GD2.CAR T-cells “conditioned” with PMN-MDSC shows downregulation of genes involved in cell activation, signal transduction, inflammation and cytokine/chemokine secretion. Analysis of NB gene-expression dataset confirms a correlation between expression of these genes and patient outcome. Moreover, in patients treated with GD2.CAR T-cells, the frequency of circulating PMN-MDSC inversely correlates with the levels of GD2.CAR T-cells, resulting more elevated in patients who did not respond or lost response to the treatment. The presence and the frequency of PMN-MDSC in PB of high-risk and metastatic NB represents a useful prognostic marker to predict the response to GD2.CAR T-cells and other adoptive immun
- Published
- 2021
10. Che-1 is targeted by c-Myc to sustain proliferation in pre-B-cell acute lymphoblastic leukemia
- Author
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Folgiero, V, and Sorino, C, and Pallocca, M, and De Nicola, F, and Goeman, F, and Bertaina, V, and Strocchio, L, Romania, P, and Pitisci, A, and Iezzi, S, And, Catena, V, and Bruno, T, and Strimpakos, G, And, Passananti, C, and Mattei, E, and Blandino, G, And, Locatelli, and F and Fanciulli, M.
- Subjects
0301 basic medicine ,Disease onset ,BCP-ALL ,Lymphoblastic Leukemia ,proliferation ,Disease ,che‐1 ,Biochemistry ,leukemogenesis ,Treatment failure ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,chemistry.chemical_compound ,RNA polymerase ,Cell Line, Tumor ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Genetics ,Medicine ,Humans ,Promoter Regions, Genetic ,Molecular Biology ,Cell Proliferation ,business.industry ,Effector ,Gene Expression Regulation, Leukemic ,High-Throughput Nucleotide Sequencing ,Pre B-cell acute lymphoblastic leukemia ,Articles ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,DNA-Binding Proteins ,Repressor Proteins ,030104 developmental biology ,c-Myc ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,bcp‐ALL ,c‐Myc ,chemistry ,Che-1 ,Direct binding ,Cancer research ,Neoplasm Recurrence, Local ,business ,Apoptosis Regulatory Proteins - Abstract
Despite progress in treating B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high‐risk relapsed patients. Che‐1/AATF (Che‐1) is an RNA polymerase II‐binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified. Here, we show that Che‐1 is overexpressed in pediatric BCP‐ALL during disease onset and at relapse, and that its depletion inhibits the proliferation of BCP‐ALL cells. Furthermore, we report that c‐Myc regulates Che‐1 expression by direct binding to its promoter and describe a strict correlation between Che‐1 expression and c‐Myc expression. RNA‐seq analyses upon Che‐1 or c‐Myc depletion reveal a strong overlap of the respective controlled pathways. Genomewide ChIP‐seq experiments suggest that Che‐1 acts as a downstream effector of c‐Myc. These results identify the pivotal role of Che‐1 in the control of BCP‐ALL proliferation and present the protein as a possible therapeutic target in children with relapsed BCP‐ALL.
- Published
- 2018
11. PB1649 EXOSOMES-MEDIATED DELIVERY OF RNA OLIGOS DIRECTED TO CHE-1/AATF IMPAIRS BCP-ALL VITALITY
- Author
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Caforio, M., primary, Sorino, C., additional, Bertaina, V., additional, Pitisci, A., additional, Battafarano, G., additional, Del Fattore, A., additional, Fanciulli, M., additional, Folgiero, V., additional, and Locatelli, F., additional
- Published
- 2019
- Full Text
- View/download PDF
12. S1635 ACADEMIC, PHASE1 TRIAL ON T CELLS EXPRESSING BOTH CD19 CHIMERIC ANTIGEN RECEPTOR AND INDUCIBLE CASPASE 9 SAFETY SWITCH FOR TREATMENT OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKAEMIA AND NON-HODGKIN LYMPHOMA
- Author
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Del Bufalo, F., primary, Merli, P., additional, Vinti, L., additional, Algeri, M., additional, Cefalo, M.G., additional, Bertaina, V., additional, Li Pira, G., additional, Caruana, I., additional, De Angelis, B., additional, Boffa, I., additional, De Cecca, S., additional, Orlando, D., additional, Guercio, M., additional, Sinibaldi, M., additional, Abbaszadeh, Z., additional, Polito, V.A., additional, Cristantielli, R., additional, Quintarelli, C., additional, and Locatelli, F., additional
- Published
- 2019
- Full Text
- View/download PDF
13. Unrelated donor vs HLA-haploidentical a/b T-cell– and B-cell–depleted HSCT in children with acute leukemia
- Author
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Bertaina, A., Zecca, M., Buldini, B., Sacchi, N., Algeri, M., Saglio, F., Perotti, C., Gallina, A. M., Bertaina, V., Lanino, E., Prete, A., Barberi, W., Tumino, M., Favre, C., Cesaro, S., Bufalo, F. D., Ripaldi, M., Boghen, S., Casazza, G., Rabusin, M., Balduzzi, A., Fagioli, F., Pagliara, D., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Bertaina, A., Zecca, M., Buldini, B., Sacchi, N., Algeri, M., Saglio, F., Perotti, C., Gallina, A. M., Bertaina, V., Lanino, E., Prete, A., Barberi, W., Tumino, M., Favre, C., Cesaro, S., Bufalo, F. D., Ripaldi, M., Boghen, S., Casazza, G., Rabusin, M., Balduzzi, A., Fagioli, F., Pagliara, D., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after ab T-cell/B-cell depletion (abhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 abhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and abhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in abhaplo-HSCT recipients (P < .001). Children treated with abhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) abhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P < .001). When compared with patients given MMUD-HSCT, abhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P < .001). These data indicate that abhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.
- Published
- 2018
14. Che-1 is targeted by c-Myc to sustain proliferation in pre-B-cell acute lymphoblastic leukemia
- Author
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Folgiero, V., Sorino, C., Pallocca, M., De Nicola, F., Goeman, F., Bertaina, V., Strocchio, L., Romania, P., Pitisci, A., Iezzi, S., Catena, V., Bruno, T., Strimpakos, G., Passananti, C., Mattei, E., Blandino, G., Locatelli, Franco, Fanciulli, M., Locatelli F. (ORCID:0000-0002-7976-3654), Folgiero, V., Sorino, C., Pallocca, M., De Nicola, F., Goeman, F., Bertaina, V., Strocchio, L., Romania, P., Pitisci, A., Iezzi, S., Catena, V., Bruno, T., Strimpakos, G., Passananti, C., Mattei, E., Blandino, G., Locatelli, Franco, Fanciulli, M., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Despite progress in treating B-cell precursor acute lymphoblastic leukemia (BCP-ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high-risk relapsed patients. Che-1/AATF (Che-1) is an RNA polymerase II-binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified. Here, we show that Che-1 is overexpressed in pediatric BCP-ALL during disease onset and at relapse, and that its depletion inhibits the proliferation of BCP-ALL cells. Furthermore, we report that c-Myc regulates Che-1 expression by direct binding to its promoter and describe a strict correlation between Che-1 expression and c-Myc expression. RNA-seq analyses upon Che-1 or c-Myc depletion reveal a strong overlap of the respective controlled pathways. Genomewide ChIP-seq experiments suggest that Che-1 acts as a downstream effector of c-Myc. These results identify the pivotal role of Che-1 in the control of BCP-ALL proliferation and present the protein as a possible therapeutic target in children with relapsed BCP-ALL.
- Published
- 2018
15. 15 - Hematopoietic Stem/Progenitor Cells and Engineering: LONG-TERM DATA ON IMMUNE MONITORING OF CHILDREN GIVEN TCRαβ/CD19 CELL DEPLETED HLA-HAPLOIDENTICAL STEM TRANSPLANTATION (HAPLO-HSCT).
- Author
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Bertaina, V., Sborgia, R., Marini, O., De Luca, C., Carta, R., Becilli, M., Pagliara, D., Quagliarella, F., Lucarelli, B., Boccieri, E., Velardi, E., Algeri, M., Merli, P., Galaverna, F., and Locatelli, F.
- Subjects
- *
HEMATOPOIETIC stem cell transplantation , *PROGENITOR cells , *ENGINEERING , *TISSUE engineering - Published
- 2023
- Full Text
- View/download PDF
16. The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood
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Bertaina, A., Vinti, L., Strocchio, L., Gaspari, S., Caruso, R., Algeri, M., Coletti, V., Gurnari, C., Romano, M., Cefalo, M. G., Girardi, K., Trevisan, V., Bertaina, V., Merli, P., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Bertaina, A., Vinti, L., Strocchio, L., Gaspari, S., Caruso, R., Algeri, M., Coletti, V., Gurnari, C., Romano, M., Cefalo, M. G., Girardi, K., Trevisan, V., Bertaina, V., Merli, P., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2–3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (1·3 mg/m2/dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty-seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 0·1%. Twenty-two of 30 BCP-ALL patients (73·3%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 31·3%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL.
- Published
- 2017
17. Outcome of children with acute leukemia given HLA-haploidentical HSCT after ab T-cell and B-cell depletion
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Locatelli, Franco, Merli, P., Pagliara, D., Li Pira, G., Falco, M., Pende, D., Rondelli, R., Lucarelli, B., Brescia, L. P., Masetti, R., Milano, G. M., Bertaina, V., Algeri, M., Pinto, R. M., Strocchio, L., Meazza, R., Grapulin, L., Handgretinger, R., Moretta, A., Bertaina, A., Moretta, L., Locatelli F. (ORCID:0000-0002-7976-3654), Locatelli, Franco, Merli, P., Pagliara, D., Li Pira, G., Falco, M., Pende, D., Rondelli, R., Lucarelli, B., Brescia, L. P., Masetti, R., Milano, G. M., Bertaina, V., Algeri, M., Pinto, R. M., Strocchio, L., Meazza, R., Grapulin, L., Handgretinger, R., Moretta, A., Bertaina, A., Moretta, L., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of ab T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti–T-lymphocyte globulin from day 25 to 23 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation–containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after ab T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
- Published
- 2017
18. Strategies to accelerate immune recovery after allogeneic hematopoietic stem cell transplantation
- Author
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Lucarelli, B., Merli, P., Bertaina, V., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Lucarelli, B., Merli, P., Bertaina, V., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
The interplay existing between immune reconstitution and patient outcome has been extensively demonstrated in allogeneic hematopoietic stem cell transplantation. One of the leading causes of infection-related mortality is the slow recovery of T-cell immunity due to the conditioning regimen and/or age-related thymus damage, poor naïve T-cell output, and restricted T-cell receptor (TCR) repertoires. With the aim of improving posttransplantation immune reconstitution, several immunotherapy approaches have been explored. Donor leukocyte infusions are widely used to accelerate immune recovery, but they carry the risk of provoking graft-versus-host disease. This review will focus on sophisticated strategies of thymus function-recovery, adoptive infusion of donor-derived, allodepleted T cells, T-cell lines/clones specific for life-threatening pathogens, regulatory T cells, and of T cells transduced with suicide genes.
- Published
- 2016
19. IDO1 involvement in mTOR pathway: A molecular mechanism of resistance to mTOR targeting in medulloblastoma
- Author
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Folgiero, V., Miele, E., Carai, A., Ferretti, E., Alfano, V., Po, A., Bertaina, V., Goffredo, B. M., Benedetti, M. C., Camassei, F. D., Cacchione, A., Locatelli, Franco, Mastronuzzi, A., Locatelli F. (ORCID:0000-0002-7976-3654), Folgiero, V., Miele, E., Carai, A., Ferretti, E., Alfano, V., Po, A., Bertaina, V., Goffredo, B. M., Benedetti, M. C., Camassei, F. D., Cacchione, A., Locatelli, Franco, Mastronuzzi, A., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite therapeutic advancements, high-risk groups still present significant mortality. A deeper knowledge of the signaling pathways contributing to MB formation and aggressiveness would help develop new successful therapies. The target of rapamycin, mTOR signaling, is known to be involved in MB and is already targetable in the clinical setting. Furthermore, mTOR is a master metabolic regulator able to control cell growth versus autophagy decisions in conditions of amino-acid deprivation that can be due to IDO1 enzymatic activity. IDO1 has been also implicated in the regulation of inflammation, as well as of T cell-mediated immune responses, in a variety of pathological conditions, including brain tumors. In particular, IDO1 induces expansion of regulatory T-cells (Treg), preventing immune response against tumor cells. Analysis of 27 MB tissue specimens for the expression of both mTOR and IDO1 showed their widespread expression in all samples. Testing their cooperation in vitro, a significant involvement of IDO1 in mTOR immunogenic pathway was found, able to counteract the aim of rapamycin treatment. In MB cell lines, inhibition of mTOR strongly induced IDO1 expression and activity, corroborating its ability to recruit Treg cells in the tumor microenvironment. The mTOR/IDO1 cross talk was found to be strictly specific of MB cells. We demonstrated that mTOR pathway cross talks with IDO1 pathway to promote MB immune escape, possibly contributing to failure of mTOR- targeted therapy.
- Published
- 2016
20. Cytomegalovirus in hematopoietic stem cell transplant recipients - management of infection
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Locatelli, Franco, Bertaina, A., Bertaina, V., Merli, P., Locatelli F. (ORCID:0000-0002-7976-3654), Locatelli, Franco, Bertaina, A., Bertaina, V., Merli, P., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Introduction: Cytomegalovirus (CMV) still causes significant morbidity and mortality in patients given allogeneic hematopoietic stem cell transplantation (HSCT). Despite effective pharmacotherapy, potentially life-threatening CMV disease occurs nowadays in up to 10% of HSCT recipients; moreover, routinely used anti-CMV agents have been shown to be associated with morbidity. Areas covered: This review examines different issues related to diagnosis and management of CMV infection in HSCT recipients, paying particular attention to the monitoring of CMV-specific immune recovery, approaches of adoptive cell therapy and new antiviral drugs. Expert commentary: Despite advances in diagnostic tests and treatment, there is still room for refining management of CMV in HSCT recipients. Immunological monitoring should be associated in the future to virological monitoring. The safety profile and efficacy of new anti-CMV agents should be compared with that of standard-of-care drugs. Donor-derived, pathogen-specific T cells adoptively transferred after transplantation could contribute to reduce the impact of CMV infection on patient’s outcome.
- Published
- 2016
21. Prevención primaria de diabetes tipo 2. Estado actual del conocimiento
- Author
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Álvarez, A., Basile, R., Bertaina, V., Caporale, Ana Julia, Castelli, Maria Victoria, Giménez, L., Guntsche, Enrique Manuel, Litwak, L., Lijteroff, G., Masciottra, Florencia, Sinay, I., and Gagliardino, Juan Jose
- Subjects
CIENCIAS MÉDICAS Y DE LA SALUD ,prevención ,Endocrinología y Metabolismo ,purl.org/becyt/ford/3.2 [https] ,prevención primaria ,diabetes tipo 2 ,purl.org/becyt/ford/3 [https] ,Medicina Clínica ,calidad de atención - Abstract
La prevalencia de diabetes ti po 2 aumenta conti nuamente a nivel mundial y su control defi ciente genera complicaciones graves que reducen la calidad de vida de quienes la padecen y elevan sus costos de atención. Sería entonces razonable pensar que para disminuir su impacto socioeconómico deberíamos mejorar la calidad de atención de las personas con diabetes y simultáneamente prevenir el desarrollo de la enfermedad en personas con alto riesgo de padecerla. Para identi fi car personas en riesgo de desarrollar diabetes se han desarrollado cuesti onarios de probada sensibilidad y especifi cidad diagnósti ca. Existe acuerdo en que identi fi cación de estas personas no produce impactos psicológicos importantes o duraderos en la población encuestada. Existen además estrategias no farmacológicas y farmacológicas capaces de prevenir/retrasar el desarrollo de diabetes en las personas en riesgo. Las primeras, consistentes en adopción de un plan de alimentación saludable y prácti ca regular de acti vidad fí sica, logran hasta un 58% de prevención y han demostrado ser efecti vas en disti ntas poblaciones (Suecia, China, Finlandia, Norteamérica e India). Su efecto preventi vo se manti ene hasta 10 años después de la intervención. Dentro de las intervenciones farmacológicas, la metf ormina, inhibidores de la α-glucosidasa (acarbosa) y las ti azolidinedionas han demostrado su efi cacia preventi va, que en general es menor que la de los cambios de esti lo de vida. Los estudios económicos concuerdan que tanto la detección por encuestas como las intervenciones preventi vas son costo-efecti vas. The prevalence of type 2 diabetes (T2DM) is conti - nuously increasing worldwide, and its poor control causes serious complicati ons that reduce the quality of life of people suff ering the disease and increase medical care costs. To decrease diabetes socio-economic impact, we should improve treatment effi cacy and simultaneously prevent its development in people at high risk. Questi onnaires with proven diagnosti c sensiti vity and specifi city have been set up to identi fy people at risk of developing diabetes, without producing important or long-lasti ng psychological impact on the surveyed populati on. Also, non-pharmacological and pharmacological strategies can be used to prevent/delay the development of diabetes in people at risk. The former, consisti ng in the adopti on of a healthy dietary plan and the practi ce of regular physical acti vity, result in up to 58% of preventi on, have been eff ecti ve in diff erent populati ons (Sweden, China, Finland, North America and India), and their preventi ve eff ect persists up to 10 years aft er the interventi on. Among pharmacological interventi ons, metf ormin, α-glucosidase inhibitors (acarbose) and thiazolidinediones have preventi ve eff ecti veness, which in general is lower than that of lifestyle changes. Economic studies agree that both, diabetes detecti on by means of surveys as well as preventi ve interventi ons are cost-eff ecti ve. Fil: Álvarez, A.. Hospital Italiano; Argentina Fil: Basile, R.. Sociedad Argentina de Nutrición; Argentina Fil: Bertaina, V.. Ministerio de Salud. Administración Nacional de Medicamentos, Alimentos y Tecnología Médica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentina Fil: Caporale, Ana Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentina Fil: Castelli, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Confederaciones de Farmacias; Argentina Fil: Giménez, L.. International Assistance Group; Francia Fil: Guntsche, Enrique Manuel. Universidad Nacional de Cuyo; Argentina Fil: Litwak, L.. Sociedad Argentina de Diabetes; Argentina Fil: Lijteroff, G.. Federación Argentina de Entidades de Lucha Contra la Diabetes; Argentina Fil: Masciottra, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentina. Ministerio de Salud. Administración Nacional de Medicamentos, Alimentos y Tecnología Médica; Argentina Fil: Sinay, I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentina. Ministerio de Salud. Administración Nacional de Medicamentos, Alimentos y Tecnología Médica; Argentina Fil: Gagliardino, Juan Jose. Ministerio de Salud. Administración Nacional de Medicamentos, Alimentos y Tecnología Médica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de la Plata. Facultad de Cs.médicas. Centro de Endocrinología Experimental y Aplicada; Argentina
- Published
- 2011
22. Differential time courses of Fos protein expression in mouse hippocampus following either acquisition or recall of an appetitive learning task
- Author
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Bertaina, V, primary and Destrade, C, additional
- Published
- 1996
- Full Text
- View/download PDF
23. K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid beta-protein precursor genes and neuronal death in rat hippocampus.
- Author
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Heurteaux, C, primary, Bertaina, V, additional, Widmann, C, additional, and Lazdunski, M, additional
- Published
- 1993
- Full Text
- View/download PDF
24. Sex-linked behavioural differences in mice expressing a human insulin transgene in the medial habenula
- Author
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Douhet, P., Bertaina, V., Durkin, T., Calas, A., and Destrade, C.
- Published
- 1997
- Full Text
- View/download PDF
25. Infusion of donor T cells transduced with inducible Caspase 9 (BPX-501 cells) is a safe and effective strategy to accelerate immune recovery in patients with non-malignant disorders after T cell depleted haplo-HSCT
- Author
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Merli, P., Bertaina, A., Li Pira, G., Pende, D., Falco, M., Pagliara, D., Bertaina, V., Sinibaldi, M., Lucarelli, B., Brescia, L. P., Milano, G. M., Cancrini, C., Montanari, M., Ceccarelli, S., Lorenzo Moretta, Moseley, A., and Locatelli, F.
26. Comparable Outcome in Children with Acute Leukemia Given Hematopoietic Stem Cell Transplantation (HSCT) either from an HLA-Compatible Sibling, an Unrelated Donor (UD) or an HLA-Haploidentical Relative after Alpha/Beta T-Cell Depletion
- Author
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Bertaina, A., Lucarelli, B., Pende, D., Pagliara, D., Merli, P., Michela Falco, Masetti, R., Rondelli, R., Bertaina, V., Cirillo, V., Brescia, L. P., Li Pira, G., Andreani, M., Grapulin, L., Montanari, M., Moretta, L., and Locatelli, F.
27. Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts
- Author
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Pietro Merli, Gianni Cazzaniga, Franco Locatelli, Vittorio Nunes, Zeinab Abbaszadeh, Alberto Orfao, Matilde Sinibaldi, Mattia Algeri, Frederikke Isa Marin, Maria Herrero-Garcia, Stefano Di Cecca, Paolo Marcatili, Biagio De Angelis, Concetta Quintarelli, Sara Gutiérrez-Herrero, Luciana Vinti, Lourdes Martín-Martín, Roselia Ciccone, Biancamaria Cembrola, Simona Songia, Simona Caruso, Iolanda Boffa, Simona Manni, Valentina Bertaina, Marika Guercio, Antonio Camera, Francesca Del Bufalo, Marco Ruella, Quintarelli, C, Guercio, M, Manni, S, Boffa, I, Sinibaldi, M, DI Cecca, S, Caruso, S, Abbaszadeh, Z, Camera, A, Cembrola, B, Ciccone, R, Orfao, A, Martin-Martin, L, Gutierrez-Herrero, S, Herrero-Garcia, M, Cazzaniga, G, Nunes, V, Songia, S, Marcatili, P, Marin, F, Ruella, M, Bertaina, V, Vinti, L, Del Bufalo, F, Algeri, M, Merli, P, De Angelis, B, Locatelli, F, Cancer Research UK, Associazione Italiana per la Ricerca sul Cancro, Asociación Española Contra el Cáncer, and Ministero della Salute
- Subjects
0301 basic medicine ,Cancer Research ,receptor ,receptors ,Epitope ,Epitopes ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Immunology and Allergy ,hematologic neoplasms ,RC254-282 ,Receptors, Chimeric Antigen ,biology ,medicine.diagnostic_test ,Chemistry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Leukemia ,Oncology ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,030220 oncology & carcinogenesis ,translational medical research ,Molecular Medicine ,immunotherapy ,Immunology ,cell engineering ,adoptive ,CD19 ,Flow cytometry ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,Leukemia, B-Cell ,medicine ,Animals ,Humans ,Pharmacology ,Immune Cell Therapies and Immune Cell Engineering ,medicine.disease ,Chimeric antigen receptor ,In vitro ,Disease Models, Animal ,030104 developmental biology ,B-cell leukemia ,chimeric antigen ,Cancer research ,biology.protein ,human activities ,hematologic neoplasm - Abstract
[Abstract]: Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells. [Methods]: We evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing. [Results]: The presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells. [Conclusions]: Taken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts., The experimental work was supported by grants awarded by Ricerca Finalizzata GR-2013 02359212 (CQ), GR-2016-02364546 (BDA), RF-2016- 02364388 (FL), Accelerator Award-Cancer Research UK/AIRC/AECC-INCAR project (FL and AO), Associazione Italiana Ricerca per la Ricerca sul Cancro (AIRC)-Special Project 5×1000 no. 9962 (FL), AIRC IG 2018 id. 21724 (FL), Ricerca Corrente (FL, CQ, BDA), Ministero dell’Università e della Ricerca (Grant PRIN 2017 to FL); Italian Healthy Ministry project on CAR T RCR-2019-23669115 (coordinator FL), Independent Research grant AIFA (FL PI: 2016 call).
- Published
- 2021
28. Unrelated donor vs HLA-haploidentical a/b T-cell– and B-cell–depleted HSCT in children with acute leukemia
- Author
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Claudio Favre, Adriana Balduzzi, Franco Locatelli, Stella Boghen, Daria Pagliara, Anna Maria Gallina, Cesare Perotti, Franca Fagioli, Nicoletta Sacchi, Barbara Buldini, Mimmo Ripaldi, Manuela Tumino, Francesco Saglio, Gabriella Casazza, Marco Zecca, Edoardo Lanino, Walter Barberi, Francesca Del Bufalo, Marco Rabusin, Alice Bertaina, Valentina Bertaina, Simone Cesaro, Mattia Algeri, Arcangelo Prete, Bertaina, A, Zecca, M, Buldini, B, Sacchi, N, Algeri, M, Saglio, F, Perotti, C, Gallina, A, Bertaina, V, Lanino, E, Prete, A, Barberi, W, Tumino, M, Favre, C, Cesaro, S, Del Bufalo, F, Ripaldi, M, Boghen, S, Casazza, G, Rabusin, M, Balduzzi, A, Fagioli, F, Pagliara, D, and Locatelli, F
- Subjects
Male ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,medicine.medical_treatment ,Biochemistry ,Immunology ,Hematology ,Cell Biology ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Gastroenterology ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Cumulative incidence ,Child ,B-Lymphocytes ,Acute leukemia ,Hematopoietic Stem Cell Transplantation ,leukemia ,Allografts ,Leukemia ,surgical procedures, operative ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Child, Preschool ,030220 oncology & carcinogenesis ,Acute Disease ,Female ,Unrelated Donors ,medicine.medical_specialty ,Adolescent ,hematopoietic stem cell transplantation ,acute leukemia ,children ,chemical and pharmacologic phenomena ,stem cell transplantation ,Lymphocyte Depletion ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Retrospective Studies ,business.industry ,haploidentical transplantation, pediatric, immune reconstitution ,Infant ,Retrospective cohort study ,pediatric, leukemia, stem cell transplantation ,medicine.disease ,Transplantation ,pediatric ,Graft-versus-host disease ,hemopoietic stem cell transplant ,Chronic Disease ,business ,030215 immunology - Abstract
Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients (P < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.
- Published
- 2018
29. Preservation of Antigen-Specific Functions of αβ T Cells and B Cells Removed from Hematopoietic Stem Cell Transplants Suggests Their Use As an Alternative Cell Source for Advanced Manipulation and Adoptive Immunotherapy
- Author
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Pietro Merli, Ignazio Caruana, Barbarella Lucarelli, Franco Locatelli, Daria Pagliara, Elia Girolami, Letizia Pomponia Brescia, Alice Bertaina, Elisabetta Cicchetti, Mauro Montanari, Stefano Di Cecca, Concetta Quintarelli, Valentina Bertaina, Giuseppina Li Pira, Simone Biagini, Pira, G. L., Cecca, S. D., Biagini, S., Girolami, E., Cicchetti, E., Bertaina, V., Quintarelli, C., Caruana, I., Lucarelli, B., Merli, P., Pagliara, D., Brescia, L. P., Bertaina, A., Montanari, M., and Locatelli, F.
- Subjects
0301 basic medicine ,Lymphocyte ,medicine.medical_treatment ,Antigen-induced activation ,HLA-haploidentical transplantation ,Immunology ,Cell ,Hematopoietic stem cell transplantation ,Streptamer ,Human leukocyte antigen ,Biology ,03 medical and health sciences ,Interleukin 21 ,medicine ,B-cell presentation ,Immunology and Allergy ,Cytotoxic T cell ,Alloreactivity ,Original Research ,Graft manipulation ,αβ T cells ,Hematopoietic stem cell ,alloreactivity ,antigen-induced activation ,graft manipulation ,030104 developmental biology ,medicine.anatomical_structure ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA - Abstract
Hematopoietic stem cell transplantation (HSCT) is standard therapy for numerous hematological diseases. The use of haploidentical donors, sharing half of the HLA alleles with the recipient, has facilitated the use of this procedure as patients can rely on availability of a haploidentical donor within their family. Since HLA disparity increases the risk of graft-versus-host disease, T-cell depletion has been used to remove alloreactive lymphocytes from the graft. Selective removal of αβ T cells, which encompass the alloreactive repertoire, combined with removal of B cells to prevent EBV-related lymphoproliferative disease, proved safe and effective in clinical studies. Depleted αβ T cells and B cells are generally discarded as by-products. Considering the possible use of donor T cells for donor lymphocyte infusions or for generation of pathogen-specific T cells as mediators of graft-versus-infection (GvI) effect, we tested whether cells in the discarded fractions were functionally intact. Response to alloantigens and to viral antigens comparable to that of unmanipulated cells indicated a functional integrity of αβ T cells, in spite of the manipulation used for their depletion. Furthermore, B cells proved to be efficient antigen-presenting cells, indicating that antigen uptake, processing and presentation were fully preserved. Therefore, we propose that separated αβ T lymphocytes could be employed for obtaining pathogen-specific T cells, applying available methods for positive selection, which eventually leads to indirect allodepletion. In addition, these functional T cells could undergo additional manipulation, such as direct allodepletion or genetic modification.
- Published
- 2017
30. Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia
- Author
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Marco Zecca, Giovanni Fernando Torelli, Andrea Pession, Valentina Folgiero, Bianca Maria Goffredo, Roberta Caruso, Riccardo Masetti, Sergio Rutella, Anna Maria Testi, Valentina Bertaina, Perla Filippini, Giuseppina Bonanno, Stefania Gaspari, Franco Locatelli, Angela Mastronuzzi, Folgiero V, Goffredo BM, Filippini P, Masetti R, Bonanno G, Caruso R, Bertaina V, Mastronuzzi A, Gaspari S, Zecca M, Torelli GF, Testi AM, Pession A, Locatelli F, and Rutella S
- Subjects
Myeloid ,Male ,analysis ,Lymphocyte ,Assay ,Fluorescent Antibody Technique ,Kaplan-Meier Estimate ,regulatory T cells ,gamma interferon, indoleamine 2 ,IDO1 ,3 dioxygenase, indoleamine 2 ,hemic and lymphatic diseases ,Indoleamine 2,3-dioxygenase ,Child ,PEDIATRIC AML ,Hematology ,Leukemia ,Blotting ,Childhood Acute Myeloid Leukemia ,Myeloid leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Child, Preschool ,Female ,Western ,Research Paper ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Adolescent ,Blotting, Western ,Enzyme-Linked Immunosorbent Assay ,Biology ,Acute ,Indoleamine-Pyrrole 2 ,Real-Time Polymerase Chain Reaction ,Disease-Free Survival ,Young Adult ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Immunoprecipitation ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Preschool ,Markers ,3 dioxygenase 1, kynurenine, STAT3 protein, tryptophan ,Acute myeloid leukemia ,immune escape ,Infant ,medicine.disease ,enzymology/mortality/pathology ,Biological ,Immunology ,Dioxygenase ,Adolescent, Assay, Blotting ,Western, Child, Child ,Preschool, Disease-Free Survival, Female, Fluorescent Antibody Technique, Humans, Immunoprecipitation, Indoleamine-Pyrrole 2 ,3 ,metabolism, Infant, Kaplan-Meier Estimate, Leukemia ,enzymology/mortality/pathology, Male, Markers ,analysis, Real-Time Polymerase Chain Reaction, Young Adult ,metabolism - Abstract
// Valentina Folgiero 1 , Bianca M. Goffredo 2 , Perla Filippini 1 , Riccardo Masetti 3 , Giuseppina Bonanno 4 , Roberta Caruso 1 , Valentina Bertaina 1 , Angela Mastronuzzi 1 , Stefania Gaspari 1 , Marco Zecca 5 , Giovanni F. Torelli 6 , Anna M. Testi 6 , Andrea Pession 3 , Franco Locatelli 1,7 , Sergio Rutella 1 1 Department of Pediatric Hematology/Oncology and Transfusion Medicine, IRCCS Bambino Gesu Children’s Hospital, Rome, Italy 2 Department of Laboratory Medicine, IRCCS Bambino Gesu Children’s Hospital, Rome, Italy 3 Department of Pediatrics, S. Orsola-Malpighi Hospital, Bologna, Italy 4 Department of Gynecology and Obstetrics, Catholic University Med. School, Rome, Italy 5 Department of Pediatric Hematology/Oncology, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy 6 Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy 7 University of Pavia, Pavia, Italy Correspondence: Sergio Rutella, email: // Keywords : Acute myeloid leukemia, IDO1, immune escape, regulatory T cells Received : October 21, 2013 Accepted : October 28, 2013 Published : October 30, 2013 Abstract Microenvironmental factors contribute to the immune dysfunction characterizing acute myeloid leukemia (AML). Indoleamine 2,3-dioxygenase 1 (IDO1) is an interferon (IFN)-γ-inducible enzyme that degrades tryptophan into kynurenine, which, in turn, inhibits effector T cells and promotes regulatory T-cell (Treg) differentiation. It is presently unknown whether childhood AML cells express IDO1 and whether IDO1 activity correlates with patient outcome. We investigated IDO1 expression and function in 37 children with newly diagnosed AML other than acute promyelocytic leukemia. Blast cells were cultured with exogenous IFN-γ for 24 hours, followed by the measurement of kynurenine production and tryptophan consumption. No constitutive expression of IDO1 protein was detected in blast cells from the 37 AML samples herein tested. Conversely, 19 out of 37 (51%) AML samples up-regulated functional IDO1 protein in response to IFN-γ. The inability to express IDO1 by the remaining 18 AML samples was not apparently due to a defective IFN-γ signaling circuitry, as suggested by the measurement of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Co-immunoprecipitation assays indicated the occurrence of physical interactions between STAT3 and IDO1 in AML blasts. In line with this finding, STAT3 inhibitors abrogated IDO1 function in AML blasts. Interestingly, levels of IFN-γ were significantly higher in the bone marrow fluid of IDO-expressing compared with IDO-nonexpressing AMLs. In mixed tumor lymphocyte cultures (MTLC), IDO-expressing AML blasts blunted the ability of allogeneic naive T cells to produce IFN-γ and promoted Treg differentiation. From a clinical perspective, the 8-year event-free survival was significantly worse in IDO-expressing children (16.4%, SE 9.8) as compared with IDO-nonexpressing ones (48.0%, SE 12.1; p =0.035). These data indicate that IDO1 expression by leukemia blasts negatively affects the prognosis of childhood AML. Moreover, they speak in favor of the hypothesis that IDO can be targeted, in adjunct to current chemotherapy approaches, to improve the clinical outcome of children with AML.
31. Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes.
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Galaverna F, Flamini S, De Luca CD, Pili I, Boccieri E, Benini F, Quagliarella F, Rosignoli C, Rosichini M, Genah S, Catanoso M, Cardinale A, Volpe G, Coccetti M, Pitisci A, Li Pira G, Carta R, Lucarelli B, Del Bufalo F, Bertaina V, Becilli M, Pagliara D, Algeri M, Merli P, Locatelli F, and Velardi E
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- Humans, Child, Adolescent, Male, Female, Young Adult, Child, Preschool, Adult, Retrospective Studies, Hematologic Neoplasms therapy, Hematologic Neoplasms immunology, Hematologic Neoplasms mortality, Infant, Treatment Outcome, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Mucosal-Associated Invariant T Cells immunology, Graft vs Host Disease etiology, Graft vs Host Disease immunology, Transplantation, Homologous
- Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematologic malignancies undergoing allogeneic (allo)-HSCT between April 2019 and May 2022, from unrelated matched donor (MUD, N=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, N=93) donor after in vitro αβT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (range, 12-49 months), overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) were 79.5%, 72%, and 7%, respectively; GvHD-free relapse-free survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While αβT cells were reconstituted 1-2 years post HSCT, MAIT cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS, and NRM were not affected by MAIT cells. Interestingly, higher MAIT cells at day +30 correlated with higher incidence of grade II-IV acute GvHD (19% vs. 7%, P=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (cGvHD) (17% vs. 6%, P=0.07) resulting in lower GRFS (55% vs. 73%, P=0.05). Higher MAIT cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs. 24%, P=0.02 and 9% vs. 18%, P=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation, and late BSI.
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- 2024
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32. Enhancer engagement sustains oncogenic transformation and progression of B-cell precursor acute lymphoblastic leukemia.
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Corleone G, Sorino C, Caforio M, Di Giovenale S, De Nicola F, Goeman F, Bertaina V, Pitisci A, Cortile C, Locatelli F, Folgiero V, and Fanciulli M
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- Humans, Child, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Enhancer Elements, Genetic, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Disease Progression
- Abstract
Background: Enhancer reprogramming plays a significant role in the heterogeneity of cancer. However, we have limited knowledge about the impact of chromatin remodeling in B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) patients, and how it affects tumorigenesis and drug response. Our research focuses on investigating the role of enhancers in sustaining oncogenic transformation in children with BCP-ALL., Methods: We used ATAC-seq to study the accessibility of chromatin in pediatric BCP-ALL at three different stages-onset, remission, and relapse. Using a combination of computational and experimental methods, we were able to analyze the accessibility landscape and focus on the most significant cis-regulatory sites. These sites were then functionally validated through the use of Promoter capture Hi-C in a primary cell line model called LAL-B, followed by RNA-seq and genomic deletion of target sites using CRISPR-Cas9 editing., Results: We found that enhancer activity changes during cancer progression and is mediated by the production of enhancer RNAs (eRNAs). CRISPR-Cas9-mediated validation of previously unknown eRNA productive enhancers demonstrated their capability to control the oncogenic activities of the MYB and DCTD genes., Conclusions: Our findings directly support the notion that productive enhancer engagement is a crucial determinant of the BCP-ALL and highlight the potential of enhancers as therapeutic targets in pediatric BCP-ALL., (© 2024. The Author(s).)
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- 2024
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33. TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis.
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Merli P, Algeri M, Galaverna F, Bertaina V, Lucarelli B, Boccieri E, Becilli M, Quagliarella F, Rosignoli C, Biagini S, Girolami E, Meschini A, Del Principe G, Sborgia R, Catanoso ML, Carta R, Strocchio L, Pinto RM, Buldini B, Falco M, Meazza R, Pende D, Andreani M, Li Pira G, Pagliara D, and Locatelli F
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- Child, Humans, Receptors, Antigen, T-Cell, alpha-beta, Transplantation, Haploidentical adverse effects, HLA Antigens, Histocompatibility Antigens Class II, Recurrence, Transplantation Conditioning methods, Retrospective Studies, Graft vs Host Disease, Leukemia, Myeloid, Acute, Hematopoietic Stem Cell Transplantation methods
- Abstract
Abstract: TCRαβ/CD19 cell depletion is a promising graft manipulation technique frequently used in the context of human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of exvivo T-cell depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median, 47.6 months for surviving patients). With a 5-year cumulative incidence of nonrelapse mortality of 5.2% (95% confidence interval [CI], 2.8%-8.8%) and a cumulative incidence of relapse of 22.7% (95% CI, 16.9%-29.2%), projected 10-year overall and disease-free survival (DFS) were 75.4% (95% CI, 68.6%-80.9%) and 71.6% (95% CI, 64.4%-77.6%), respectively. Cumulative incidence of both grade II-IV acute and chronic graft-versus-host disease were low (14.7% and 8.1%, respectively). In a multivariable analysis for DFS including type of disease, use of total body irradiation in the conditioning regimen (hazard ratio [HR], 0.5; 95% CI, 0.26-0.98; P = .04), disease status at HSCT (complete remission [CR] ≥3 vs CR 1/2; HR, 2.23; 95% CI, 1.20-4.16; P = .01), and high levels of pre-HSCT minimal residual disease (HR, 2.09; 95% CI, 1.01-4.33; P = .04) were independently associated with outcome. In summary, besides confirming the good outcome results already reported (which are almost superimposable on those of transplant from HLA-matched donors), this clinical update allows the identification of patients at higher risk of treatment failure for whom personalized approaches, aimed at reducing the risk of relapse, are warranted., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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34. Achievement of operational tolerance in a pediatric liver transplant recipient following successful hematopoietic stem cell transplantation from a different donor.
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Algeri M, Velardi E, Spada M, Galaverna F, Carta R, Vinti L, Palumbo G, Gaspari S, Pietrobattista A, Boccieri E, Becilli M, Francalanci P, Bertaina V, Merli P, and Locatelli F
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- Male, Humans, Child, Tissue Donors, Immune Tolerance, Transplantation, Homologous adverse effects, Liver Transplantation adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Anemia, Aplastic etiology, Graft vs Host Disease etiology
- Abstract
Hematopoietic stem cell transplantation (HSCT)-based approaches are increasingly investigated strategies to induce tolerance in recipients of solid allografts. However, in the majority of cases, these approaches rely on the infusion of hematopoietic stem cells recovered from the same solid organ donor. In this report, we describe the case of a boy who received liver transplantation from a deceased donor, who had successfully underwent allogeneic HSCT from an unrelated donor for hepatitis-associated aplastic anemia. In this patient, it was possible to permanently withdraw post-HSCT immune suppression without causing any sign of liver graft dysfunction. To the best of our knowledge, this is the first case of operational tolerance documented in a patient who received combined liver transplantation and HSCT from different donors., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)
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- 2023
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35. Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL.
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Del Bufalo F, Becilli M, Rosignoli C, De Angelis B, Algeri M, Hanssens L, Gunetti M, Iacovelli S, Li Pira G, Girolami E, Leone G, Lazzaro S, Bertaina V, Sinibaldi M, Di Cecca S, Iaffaldano L, Künkele A, Boccieri E, Del Baldo G, Pagliara D, Merli P, Carta R, Quintarelli C, and Locatelli F
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- Young Adult, Humans, Child, T-Lymphocytes, Immunotherapy, Adoptive adverse effects, Antigens, CD19, Hematopoietic Stem Cell Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Graft vs Host Disease etiology
- Abstract
Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or displaying profound lymphopenia and/or rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T cells transduced with a second-generation (4.1BB) CD19-directed CAR for treatment of patients with BCP-ALL in a hospital-exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR-Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy-based manufacturing process (CD19-CAR-Lenti_ALLO). Thirteen children/young adults received ALLO-CAR-T cells between March 2021 and October 2022. Doses ranged between 1.0 × 106 and 3.0 × 106 CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell-associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO-CAR-T cells from an HLA-haploidentical donor, experienced GVHD. Two patients received ALLO-CAR-T cells before HSCT and showed a significant expansion of CAR-T cells without any sign of GVHD. All patients obtained complete remission (CR) with absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells., (© 2023 by The American Society of Hematology.)
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- 2023
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36. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma.
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Del Bufalo F, De Angelis B, Caruana I, Del Baldo G, De Ioris MA, Serra A, Mastronuzzi A, Cefalo MG, Pagliara D, Amicucci M, Li Pira G, Leone G, Bertaina V, Sinibaldi M, Di Cecca S, Guercio M, Abbaszadeh Z, Iaffaldano L, Gunetti M, Iacovelli S, Bugianesi R, Macchia S, Algeri M, Merli P, Galaverna F, Abbas R, Garganese MC, Villani MF, Colafati GS, Bonetti F, Rabusin M, Perruccio K, Folsi V, Quintarelli C, and Locatelli F
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- Child, Humans, Caspase 9 adverse effects, Caspase 9 genetics, Caspase 9 metabolism, Caspase 9 therapeutic use, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local therapy, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Neuroblastoma genetics, Neuroblastoma therapy, Receptors, Chimeric Antigen therapeutic use
- Abstract
Background: Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma., Methods: In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01)., Results: A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×10
6 CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×106 CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively., Conclusions: The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT03373097.)., (Copyright © 2023 Massachusetts Medical Society.)- Published
- 2023
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37. Inflammatory status in pediatric sickle cell disease: Unravelling the role of immune cell subsets.
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Marchesani S, Bertaina V, Marini O, Cossutta M, Di Mauro M, Rotulo GA, Palma P, Sabatini L, Petrone MI, Frati G, Monteleone G, Palumbo G, and Ceglie G
- Abstract
Introduction: The mutation of the beta-globin gene that causes sickle cell disease (SCD) results in pleiotropic effects, such as hemolysis and vaso-occlusive crisis that can induce inflammatory mechanisms with deleterious consequences on the organism. Moreover, SCD patients display an increased susceptibility to infections. Few studies are currently available that evaluate a wide immunological profile in a pediatric population. This study proposes an evaluation of the immune profile in subjects with SCD in a pediatric population through a detailed analysis by flow cytometry. Methods and Materials: Peripheral blood samples from 53 pediatric patients with SCD (mean age 9.8 years, interquartile range 9 years) were obtained and then analyzed by flow cytometry, in order to evaluate changes in the immune populations compared to 40 healthy donors (mean age 7.3 years, interquartile range 9.5 years). Results: Our data showed an increase in neutrophils (with a reduction in the CD62L + subpopulation) and monocytes (with a decrease in HLA-DRlow monocytes) with normal values of lymphocytes in SCD patients. In the lymphocyte subpopulations analysis we observed lower values of CD4
+ T cells (with higher number of memory and central memory T lymphocytes) with increased frequency of CD8+ T cells (with a predominant naive pattern). Moreover, we observed higher values of CD39+ Tregs and lower HLA-DR+ and CD39- T cells with an increased Th17, Th1-17 and Th2 response. Conclusion: We observed immunological alterations typical of an inflammatory status (increase in activated neutrophils and monocytes) associated with a peculiar Treg pattern (probably linked to a body attempt to minimize inflammation intrinsic to SCD). Furthermore, we highlighted a T helper pathway associated with inflammation in line with other studies. Our data showed that immunological markers may have an important role in the understanding the pathophysiology of SCD and in optimizing targeted therapeutic strategies for each patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marchesani, Bertaina, Marini, Cossutta, Di Mauro, Rotulo, Palma, Sabatini, Petrone, Frati, Monteleone, Palumbo and Ceglie.)- Published
- 2023
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38. Immunological profile in a pediatric population of patients with spherocytosis. A single-center experience.
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Marchesani S, Sabatini L, Bertaina V, Marini O, Ambrosi M, Di Mauro M, Cossutta M, Schettini L, Lodi M, Rotulo GA, Palma P, Palumbo G, and Ceglie G
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- Child, Humans, Splenectomy, Spleen, Erythrocyte Count, Erythrocytes, Spherocytosis, Hereditary surgery
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Spherocytosis is a hereditary disease caused by the deficiencies of different membrane proteins of red blood cells. Currently, splenectomy is the main therapeutic strategy available, although it is accompanied by an increased risk of sepsis. Several evidences have supported the hypothesis of spleen dysfunction in patients with spherocytosis that haven't yet undergone splenectomy. The aim of this study is to furtherly characterize this aspect, by describing the immune subpopulations in peripheral blood samples obtained from 41 pediatric patients with hereditary spherocytosis by flow cytometry, in order to evaluate changes in the composition of the immune populations compared to 16 healthy donors. Patients were divided in two groups: splenectomized and non-splenectomized. In the splenectomized population, data showed neutrophilic leukocytosis, thrombocytosis, increase in NK and reduction in CD4+ lymphocytes. However, we observed that most of the results obtained in the splenectomized group were found in the non-splenectomized patients as well (increase in neutrophils, in NK, reduction of CD19+, CD4+ lymphocytes and CD4+ and CD8+ naïve cells). The alterations of the immune system may be mainly due to the disease itself, regardless of splenectomy. Therefore, immunological criteria could be included in clinical phenotype assessment in order to better optimize the timing for splenectomy., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier Inc.)
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- 2023
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39. αβT- and B-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation in children with myelodysplastic syndromes.
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Merli P, Pagliara D, Mina T, Bertaina V, Li Pira G, Lazzaro S, Biagini S, Galaverna F, Strocchio L, Carta R, Catanoso ML, Quagliarella F, Becilli M, Boccieri E, Del Bufalo F, Panigari A, Agostini A, Pedace L, Pizzi S, Perotti C, Algeri M, Zecca M, and Locatelli F
- Subjects
- Child, Humans, B-Lymphocytes, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Myelodysplastic Syndromes therapy
- Published
- 2022
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40. Expansion of CD4dimCD8+ T cells characterizes macrophage activation syndrome and other secondary HLH.
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De Matteis A, Colucci M, Rossi MN, Caiello I, Merli P, Tumino N, Bertaina V, Pardeo M, Bracaglia C, Locatelli F, De Benedetti F, and Prencipe G
- Subjects
- Child, Humans, Leukocytes, Mononuclear pathology, Prospective Studies, Arthritis, Juvenile complications, Lymphohistiocytosis, Hemophagocytic pathology, Macrophage Activation Syndrome pathology
- Abstract
CD8+ T-cell activation has been demonstrated to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (HLH) from patients with early sepsis. We evaluated the activation profile of CD8+ T cells in patients with various forms of secondary HLH (sHLH), including macrophage activation syndrome (MAS). Peripheral blood mononuclear cells from children with inactive systemic juvenile idiopathic arthritis (sJIA, n = 17), active sJIA (n = 27), MAS in sJIA (n = 14), infection-associated HLH (n = 7), and with other forms of sHLH (n = 9) were analyzed by flow cytometry. Compared with patients with active sJIA, in patients with MAS and sHLH of different origins, beside a significant increase in the frequency of CD38high/HLA-DR+CD8+ T cells, we found a significant increase in the frequency of CD8+ T cells expressing the CD4 antigen (CD4dimCD8+ T cells). These cells expressed high levels of the activation markers CD38 and HLA-DR, suggesting they were a subset of CD38high/HLA-DR+CD8+ T cells, as well as of the activation/exhaustion markers CD25, PD1, CD95, and interferon-γ. The frequency of CD4dimCD8+ T cells strongly correlated with most of the laboratory parameters of MAS severity and with circulating levels of CXCL9 and interleukin-18. These findings were confirmed in a prospective replication cohort in which no expansion of any particular T-cell receptor Vβ family in CD3+ T cells of patients with sHLH was found. Finally, frequency of CD4dimCD8+, but not of CD38high/HLA-DR+CD8+ T cells, significantly correlated with a clinical severity score, further supporting the involvement of these cells in MAS/sHLH pathogenesis., (© 2022 by The American Society of Hematology.)
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- 2022
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41. Comprehensive phenotyping of human peripheral blood B lymphocytes in pathological conditions.
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Carsetti R, Corrente F, Capponi C, Mirabella M, Cascioli S, Palomba P, Bertaina V, Pagliara D, Colucci M, and Piano Mortari E
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- Flow Cytometry, Humans, B-Lymphocyte Subsets, B-Lymphocytes
- Abstract
Several diseases are associated with alterations of the B-cell compartment. Knowing how to correctly identify by flow cytometry the distribution of B-cell populations in the peripheral blood is important to help in the early diagnosis. In the accompanying article we describe how to identify the different B-cell subsets in the peripheral blood of healthy donors. Here we show a few examples of diseases that cause dysregulation of the B-cell compartment., (© 2021 The Authors. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.)
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- 2022
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42. TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders.
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Merli P, Pagliara D, Galaverna F, Li Pira G, Andreani M, Leone G, Amodio D, Pinto RM, Bertaina A, Bertaina V, Mastronuzzi A, Strocchio L, Boccieri E, Pende D, Falco M, Di Nardo M, Del Bufalo F, Algeri M, and Locatelli F
- Subjects
- Adolescent, Child, Child, Preschool, Humans, Infant, Prospective Studies, Receptors, Antigen, T-Cell, alpha-beta, Transplantation Conditioning, Treatment Outcome, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Several nonmalignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders, or metabolic diseases, lacking a fully matched donor or requiring urgent transplantation underwent TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study. The median age at transplant was 3.5 years (range 0.3-16.1); the median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (eg, aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at the time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade 1-2 acute GVHD was 14.4% (no patient developed grade 3-4 acute GVHD). Only one patient at risk developed mild chronic GVHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment of children with NMDs. Prompt donor availability, low incidence of GVHD, and TRM make this strategy an attractive option in NMDs patients. The study is registered at ClinicalTrial.gov as NCT01810120., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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43. Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma.
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Tumino N, Weber G, Besi F, Del Bufalo F, Bertaina V, Paci P, Quatrini L, Antonucci L, Sinibaldi M, Quintarelli C, Maggi E, De Angelis B, Locatelli F, Moretta L, Vacca P, and Caruana I
- Subjects
- Humans, Myeloid-Derived Suppressor Cells pathology, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Neuroblastoma immunology, Neuroblastoma pathology, Treatment Outcome, Immunotherapy, Adoptive methods, Myeloid-Derived Suppressor Cells immunology, Neuroblastoma therapy
- Abstract
The outcome of patients affected by high-risk or metastatic neuroblastoma (NB) remains grim, with ≥ 50% of the children experiencing relapse or progression of the disease despite multimodal, intensive treatment. In order to identify new strategies to improve the overall survival and the quality of life of these children, we recently developed and optimized a third-generation GD2-specific chimeric antigen receptor (CAR) construct, which is currently under evaluation in our Institution in a phase I/II clinical trial (NCT03373097) enrolling patients with relapsed/refractory NB. We observed that our CAR T-cells are able to induce marked tumor reduction and even achieve complete remission with a higher efficiency than that of other CAR T-cells reported in previous studies. However, often responses are not sustained and relapses occur. Here, we demonstrate for the first time a mechanism of resistance to GD2.CAR T-cell treatment, showing how polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) increase in the peripheral blood (PB) of NB patients after GD2.CAR T-cell treatment in case of relapse and loss of response. In vitro, isolated PMN-MDSC demonstrate to inhibit the anti-tumor cytotoxicity of different generations of GD2.CAR T-cells. Gene-expression profiling of GD2.CAR T-cells "conditioned" with PMN-MDSC shows downregulation of genes involved in cell activation, signal transduction, inflammation and cytokine/chemokine secretion. Analysis of NB gene-expression dataset confirms a correlation between expression of these genes and patient outcome. Moreover, in patients treated with GD2.CAR T-cells, the frequency of circulating PMN-MDSC inversely correlates with the levels of GD2.CAR T-cells, resulting more elevated in patients who did not respond or lost response to the treatment. The presence and the frequency of PMN-MDSC in PB of high-risk and metastatic NB represents a useful prognostic marker to predict the response to GD2.CAR T-cells and other adoptive immunotherapy. This study underlines the importance of further optimization of both CAR T-cells and clinical trial in order to target elements of the tumor microenvironment., (© 2021. The Author(s).)
- Published
- 2021
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44. Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts.
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Quintarelli C, Guercio M, Manni S, Boffa I, Sinibaldi M, Di Cecca S, Caruso S, Abbaszadeh Z, Camera A, Cembrola B, Ciccone R, Orfao A, Martin-Martin L, Gutierrez-Herrero S, Herrero-Garcia M, Cazzaniga G, Nunes V, Songia S, Marcatili P, Marin FI, Ruella M, Bertaina V, Vinti L, Del Bufalo F, Algeri M, Merli P, De Angelis B, and Locatelli F
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Humans, Mice, Epitopes immunology, Leukemia, B-Cell immunology, Receptors, Chimeric Antigen immunology
- Abstract
Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells., Background: METHODS: We evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing., Results: The presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells., Conclusions: Taken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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45. HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia.
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Strocchio L, Pagliara D, Algeri M, Li Pira G, Rossi F, Bertaina V, Leone G, Pinto RM, Andreani M, Agolini E, Girardi K, Gaspari S, Grapulin L, Del Bufalo F, Novelli A, Merli P, and Locatelli F
- Subjects
- Child, Humans, Prospective Studies, Receptors, Antigen, T-Cell, alpha-beta, Transplantation Conditioning, Young Adult, Fanconi Anemia therapy, Hematopoietic Stem Cell Transplantation
- Abstract
We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell-depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120., (© 2021 by The American Society of Hematology.)
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- 2021
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46. Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia.
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Merli P, Algeri M, Galaverna F, Milano GM, Bertaina V, Biagini S, Girolami E, Palumbo G, Sinibaldi M, Becilli M, Leone G, Boccieri E, Grapulin L, Gaspari S, Airoldi I, Strocchio L, Pagliara D, and Locatelli F
- Subjects
- Adolescent, B-Lymphocytes immunology, Child, Child, Preschool, Cohort Studies, Disease-Free Survival, Feasibility Studies, Female, Graft vs Host Disease immunology, Graft vs Host Disease prevention & control, Humans, Immunologic Factors adverse effects, Infant, Male, T-Lymphocytes immunology, Transplantation, Homologous methods, Young Adult, Zoledronic Acid adverse effects, Antigens, CD19 immunology, Hematopoietic Stem Cell Transplantation methods, Immunologic Factors administration & dosage, Leukemia, Myeloid, Acute therapy, Lymphocyte Depletion methods, Receptors, Antigen, T-Cell, alpha-beta immunology, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocytes drug effects, Transplantation Conditioning methods, Transplantation, Haploidentical methods, Zoledronic Acid administration & dosage
- Abstract
TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24-48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, p = 0.015) and chronic GvHD (0 vs. 22.2%, p = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, p = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, p = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1-2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, p = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, p = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM., (Copyright © 2020 Merli, Algeri, Galaverna, Milano, Bertaina, Biagini, Girolami, Palumbo, Sinibaldi, Becilli, Leone, Boccieri, Grapulin, Gaspari, Airoldi, Strocchio, Pagliara and Locatelli.)
- Published
- 2020
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47. Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia.
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Bertaina A, Zecca M, Buldini B, Sacchi N, Algeri M, Saglio F, Perotti C, Gallina AM, Bertaina V, Lanino E, Prete A, Barberi W, Tumino M, Favre C, Cesaro S, Del Bufalo F, Ripaldi M, Boghen S, Casazza G, Rabusin M, Balduzzi A, Fagioli F, Pagliara D, and Locatelli F
- Subjects
- Acute Disease, Adolescent, Allografts, Child, Child, Preschool, Chronic Disease, Female, Humans, Infant, Male, Retrospective Studies, B-Lymphocytes, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation, Leukemia mortality, Leukemia therapy, Lymphocyte Depletion, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Unrelated Donors
- Abstract
Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients ( P < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD ( P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively ( P < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS ( P < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available., (© 2018 by The American Society of Hematology.)
- Published
- 2018
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48. Che-1 is targeted by c-Myc to sustain proliferation in pre-B-cell acute lymphoblastic leukemia.
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Folgiero V, Sorino C, Pallocca M, De Nicola F, Goeman F, Bertaina V, Strocchio L, Romania P, Pitisci A, Iezzi S, Catena V, Bruno T, Strimpakos G, Passananti C, Mattei E, Blandino G, Locatelli F, and Fanciulli M
- Subjects
- Cell Line, Tumor, Cell Proliferation genetics, DNA-Binding Proteins genetics, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Humans, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Promoter Regions, Genetic genetics, Apoptosis Regulatory Proteins genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Proteins c-myc genetics, Repressor Proteins genetics
- Abstract
Despite progress in treating B-cell precursor acute lymphoblastic leukemia (BCP-ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high-risk relapsed patients. Che-1/AATF (Che-1) is an RNA polymerase II-binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified. Here, we show that Che-1 is overexpressed in pediatric BCP-ALL during disease onset and at relapse, and that its depletion inhibits the proliferation of BCP-ALL cells. Furthermore, we report that c-Myc regulates Che-1 expression by direct binding to its promoter and describe a strict correlation between Che-1 expression and c-Myc expression. RNA-seq analyses upon Che-1 or c-Myc depletion reveal a strong overlap of the respective controlled pathways. Genomewide ChIP-seq experiments suggest that Che-1 acts as a downstream effector of c-Myc. These results identify the pivotal role of Che-1 in the control of BCP-ALL proliferation and present the protein as a possible therapeutic target in children with relapsed BCP-ALL., (© 2018 The Authors.)
- Published
- 2018
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49. Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.
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Locatelli F, Merli P, Pagliara D, Li Pira G, Falco M, Pende D, Rondelli R, Lucarelli B, Brescia LP, Masetti R, Milano GM, Bertaina V, Algeri M, Pinto RM, Strocchio L, Meazza R, Grapulin L, Handgretinger R, Moretta A, Bertaina A, and Moretta L
- Subjects
- Acute Disease, Adolescent, Adult, Allografts, Antilymphocyte Serum administration & dosage, Child, Child, Preschool, Disease-Free Survival, Female, Follow-Up Studies, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Humans, Infant, Male, Survival Rate, B-Lymphocytes, Hematopoietic Stem Cell Transplantation, Leukemia mortality, Leukemia therapy, Lymphocyte Depletion, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes
- Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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50. Preservation of Antigen-Specific Functions of αβ T Cells and B Cells Removed from Hematopoietic Stem Cell Transplants Suggests Their Use As an Alternative Cell Source for Advanced Manipulation and Adoptive Immunotherapy.
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Li Pira G, Di Cecca S, Biagini S, Girolami E, Cicchetti E, Bertaina V, Quintarelli C, Caruana I, Lucarelli B, Merli P, Pagliara D, Brescia LP, Bertaina A, Montanari M, and Locatelli F
- Abstract
Hematopoietic stem cell transplantation is standard therapy for numerous hematological diseases. The use of haploidentical donors, sharing half of the HLA alleles with the recipient, has facilitated the use of this procedure as patients can rely on availability of a haploidentical donor within their family. Since HLA disparity increases the risk of graft-versus-host disease, T-cell depletion has been used to remove alloreactive lymphocytes from the graft. Selective removal of αβ T cells, which encompass the alloreactive repertoire, combined with removal of B cells to prevent EBV-related lymphoproliferative disease, proved safe and effective in clinical studies. Depleted αβ T cells and B cells are generally discarded as by-products. Considering the possible use of donor T cells for donor lymphocyte infusions or for generation of pathogen-specific T cells as mediators of graft-versus-infection effect, we tested whether cells in the discarded fractions were functionally intact. Response to alloantigens and to viral antigens comparable to that of unmanipulated cells indicated a functional integrity of αβ T cells, in spite of the manipulation used for their depletion. Furthermore, B cells proved to be efficient antigen-presenting cells, indicating that antigen uptake, processing, and presentation were fully preserved. Therefore, we propose that separated αβ T lymphocytes could be employed for obtaining pathogen-specific T cells, applying available methods for positive selection, which eventually leads to indirect allodepletion. In addition, these functional T cells could undergo additional manipulation, such as direct allodepletion or genetic modification.
- Published
- 2017
- Full Text
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