286 results on '"Quintarelli C"'
Search Results
2. T2EVOLVE: STANDARDIZATION OF PRE-CLINICAL AND CLINICAL DEVELOPMENT OF ENGINEERED T CELL THERAPY IN EUROPE; A CROSS FUNCTIONAL MULTI STAKEHOLDER INITIATIVE
- Author
-
Luu, M., primary, Sanges, C., additional, Dreuillet, C., additional, Pennings, E., additional, Casucci, M., additional, Franz, P., additional, Donnadieu, E., additional, Quintarelli, C., additional, Guedan, S., additional, Kersten, M., additional, Morris, E., additional, Ivics, Z., additional, Jager, U., additional, Busch, D.H., additional, Gonzalez, E., additional, Paiva, B., additional, Schröder, B., additional, Chu, L., additional, Cabrizo, Y., additional, Ammar, D., additional, Junius, S., additional, Philippar, U., additional, Fleischer, A., additional, Awigena-Cook, J., additional, Schapitz, I., additional, Henderson, D., additional, Kremer, A., additional, Wagers, S., additional, Choudhary, R., additional, and Hudecek, M., additional
- Published
- 2024
- Full Text
- View/download PDF
3. Process Development and Manufacturing: OUTCOMES OF THE T2EVOLVE EUROPEAN SURVEY ON CAR T CELL ANALYTICAL METHODS FROM APHERESIS TO POST-INFUSION IMMUNOMONITORING
- Author
-
Lecot, P., primary, Courcault, E., additional, Neininger, K., additional, Lorrain, M., additional, Gambotti, L., additional, Dreuillet, C., additional, Chatterjee, S., additional, Locatelli, F., additional, Luu, M., additional, Sanges, C., additional, Hudecek, M., additional, Kremer, A., additional, De Angelis, B., additional, Quintarelli, C., additional, and Negre, H., additional
- Published
- 2023
- Full Text
- View/download PDF
4. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma
- Author
-
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
5. Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL
- Author
-
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
6. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. Reply
- Author
-
Quintarelli, C., Del Bufalo, F., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Quintarelli, C., Del Bufalo, F., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
To the Editor: Del Bufalo et al. (April 6 issue)(1) describe the treatment of patients with relapsed or refractory pediatric neuroblastoma with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 and express the inducible capsase 9 suicide gene (GD2-CART01). Among the children who had a relapse after this treatment, the authors did not observe reexpansion of T cells, and the GD2 antigen was still expressed on tumor cells. We were surprised by the surface-marker analysis of the GD2-CAR T cells that led the authors to conclude that these cells were not exhausted. The data show that the . . .
- Published
- 2023
7. The response to BTN62b2 booster doses demonstrates that serum antibodies do not predict the establishment of immune B-cell memory in common variable immune deficiencies
- Author
-
Piano Mortari, E., primary, Pulvirenti, F., additional, Marcellini, V., additional, Terreri, S., additional, Fernandez Salinas, A., additional, Ferrari, S., additional, Di Napoli, G., additional, Guadagnolo, D., additional, Sculco, E., additional, Albano, C., additional, Guercio, M., additional, Di Cecca, S., additional, Milito, C., additional, Garzi, G., additional, Pesce, A.M., additional, Bonanni, L., additional, Sinibaldi, M., additional, Di Cecilia, S., additional, Agrati, C., additional, Quintarelli, C., additional, Zaffina, S., additional, Locatelli, F., additional, Carsetti, R., additional, and Quinti, I., additional
- Published
- 2022
- Full Text
- View/download PDF
8. 443 T-cell repertoire in metastatic melanoma patients developing skin leukoderma after treatment with checkpoint inhibitors
- Author
-
Carbone, M., primary, Capone, A., additional, Guercio, M., additional, Reddel, S., additional, Lulli, D., additional, Feudi, E., additional, Volpe, E., additional, Quintarelli, C., additional, and Failla, C.M., additional
- Published
- 2022
- Full Text
- View/download PDF
9. Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts
- Author
-
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
10. The immune response as a double-edged sword: The lesson learnt during the COVID-19 pandemic
- Author
-
Agrati, C., Carsetti, R., Bordoni, V., Sacchi, A., Quintarelli, C., Locatelli, Franco, Ippolito, G., Capobianchi, M. R., Locatelli F. (ORCID:0000-0002-7976-3654), Agrati, C., Carsetti, R., Bordoni, V., Sacchi, A., Quintarelli, C., Locatelli, Franco, Ippolito, G., Capobianchi, M. R., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
The COVID-19 pandemic has represented an unprecedented challenge for the humanity, and scientists around the world provided a huge effort to elucidate critical aspects in the fight against the pathogen, useful in designing public health strategies, vaccines and therapeutic approaches. One of the first pieces of evidence characterizing the SARS-CoV-2 infection has been its breadth of clinical presentation, ranging from asymptomatic to severe/deadly disease, and the indication of the key role played by the immune response in influencing disease severity. This review is aimed at summarizing what the SARS-CoV-2 infection taught us about the immune response, highlighting its features of a double-edged sword mediating both protective and pathogenic processes. We will discuss the protective role of soluble and cellular innate immunity and the detrimental power of a hyper-inflammation-shaped immune response, resulting in tissue injury and immunothrombotic events. We will review the importance of B- and T-cell immunity in reducing the clinical severity and their ability to cross-recognize viral variants.
- Published
- 2022
11. Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML
- Author
-
Pianigiani, G., Gagliardi, A., Mezzasoma, F., Rocchio, F., Tini, V., Bigerna, B., Sportoletti, P., Caruso, S., Marra, A., Peruzzi, S., Petito, E., Spinozzi, G., Shacham, S., Landesman, Y., Quintarelli, C., Gresele, P., Locatelli, Franco, Martelli, M. P., Falini, B., Brunetti, L., Locatelli F. (ORCID:0000-0002-7976-3654), Pianigiani, G., Gagliardi, A., Mezzasoma, F., Rocchio, F., Tini, V., Bigerna, B., Sportoletti, P., Caruso, S., Marra, A., Peruzzi, S., Petito, E., Spinozzi, G., Shacham, S., Landesman, Y., Quintarelli, C., Gresele, P., Locatelli, Franco, Martelli, M. P., Falini, B., Brunetti, L., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
NPM1 is the most frequently mutated gene in adults with acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and exportin-1 (XPO1) causes aberrant cytoplasmic dislocation of NPM1c and promotes the high expression of homeobox (HOX) genes, which is critical for maintaining the leukemic state of NPM1-mutated cells. Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in patients with NPM1 mutations. Here, we show that this dosing strategy results in only a temporary disruption of the XPO1-NPM1c interaction, limiting the efficacy of selinexor. Because the second-generation XPO1 inhibitor eltanexor can be administered more frequently, we tested the antileukemic activity of prolonged XPO1 inhibition in NPM1-mutated AML models. Eltanexor caused irreversible HOX downregulation, induced terminal AML differentiation, and prolonged the survival of leukemic mice. This study provides essential information for the appropriate design of clinical trials with XPO1 inhibitors in NPM1-mutated AML.
- Published
- 2022
12. Time to evolve: predicting engineered T cell-associated toxicity with next-generation models
- Author
-
Donnadieu, E., Luu, M., Alb, M., Anliker, B., Arcangeli, S., Bonini, C., De Angelis, B., Choudhary, R., Espie, D., Galy, A., Holland, C., Ivics, Z., Kantari-Mimoun, C., Kersten, M. J., Kohl, U., Kuhn, C., Laugel, B., Locatelli, Franco, Marchiq, I., Markman, J., Moresco, M. A., Morris, E., Negre, H., Quintarelli, C., Rade, M., Reiche, K., Renner, M., Ruggiero, E., Sanges, C., Stauss, H., Themeli, M., Van den Brulle, J., Hudecek, M., Casucci, M., Locatelli F. (ORCID:0000-0002-7976-3654), Donnadieu, E., Luu, M., Alb, M., Anliker, B., Arcangeli, S., Bonini, C., De Angelis, B., Choudhary, R., Espie, D., Galy, A., Holland, C., Ivics, Z., Kantari-Mimoun, C., Kersten, M. J., Kohl, U., Kuhn, C., Laugel, B., Locatelli, Franco, Marchiq, I., Markman, J., Moresco, M. A., Morris, E., Negre, H., Quintarelli, C., Rade, M., Reiche, K., Renner, M., Ruggiero, E., Sanges, C., Stauss, H., Themeli, M., Van den Brulle, J., Hudecek, M., Casucci, M., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, including humanized mouse models, which can better recapitulate toxicities observed in patients. The Accelerating Development and Improving Access to CAR and TCR-engineered T cell therapy (T2EVOLVE) consortium is a public-private partnership directed at accelerating the preclinical development and increasing access to engineered T-cell therapy for patients with cancer. A key ambition in T2EVOLVE is to design new models and tools with higher predictive value for clinical safety and efficacy, in order to improve and accelerate the selection of lead T-cell products for clinical translation. Herein, we review existing preclinical models that are used to test the safety of engineered T cells. We will also highlight limitations of these models and propose potential measures to improve them.
- Published
- 2022
13. Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant
- Author
-
De Billy, E., Pellegrino, M., Orlando, D., Pericoli, G., Ferretti, R., Businaro, P., Ajmone-Cat, M. A., Rossi, S., Petrilli, L. L., Maestro, N., Diomedi-Camassei, F., Pezzullo, M., De Stefanis, C., Bencivenga, P., Palma, A., Rota, R., Del Bufalo, F., Massimi, Luca, Weber, G., Jones, C., Carai, A., Caruso, S., De Angelis, B., Caruana, I., Quintarelli, C., Mastronuzzi, A., Locatelli, Franco, Vinci, M., Massimi L., Locatelli F. (ORCID:0000-0002-7976-3654), De Billy, E., Pellegrino, M., Orlando, D., Pericoli, G., Ferretti, R., Businaro, P., Ajmone-Cat, M. A., Rossi, S., Petrilli, L. L., Maestro, N., Diomedi-Camassei, F., Pezzullo, M., De Stefanis, C., Bencivenga, P., Palma, A., Rota, R., Del Bufalo, F., Massimi, Luca, Weber, G., Jones, C., Carai, A., Caruso, S., De Angelis, B., Caruana, I., Quintarelli, C., Mastronuzzi, A., Locatelli, Franco, Vinci, M., Massimi L., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Diffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy. Methods: Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function. Results: GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo. Conclusion: Our study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.
- Published
- 2022
14. Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies
- Author
-
Garcia-Prieto, C. A., Villanueva, L., Bueno-Costa, A., Davalos, V., Gonzalez-Navarro, E. A., Juan, M., Urbano-Ispizua, A., Delgado, J., Ortiz-Maldonado, V., Del Bufalo, F., Locatelli, Franco, Quintarelli, C., Sinibaldi, M., Soler, M., Castro De Moura, M., Ferrer, G., Urdinguio, R. G., Fernandez, A. F., Fraga, M. F., Bar, D., Meir, A., Itzhaki, O., Besser, M. J., Avigdor, A., Jacoby, E., Esteller, M., Locatelli F. (ORCID:0000-0002-7976-3654), Garcia-Prieto, C. A., Villanueva, L., Bueno-Costa, A., Davalos, V., Gonzalez-Navarro, E. A., Juan, M., Urbano-Ispizua, A., Delgado, J., Ortiz-Maldonado, V., Del Bufalo, F., Locatelli, Franco, Quintarelli, C., Sinibaldi, M., Soler, M., Castro De Moura, M., Ferrer, G., Urdinguio, R. G., Fernandez, A. F., Fraga, M. F., Bar, D., Meir, A., Itzhaki, O., Besser, M. J., Avigdor, A., Jacoby, E., Esteller, M., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods: We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided. Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P <. 001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P =. 002; log-rank P =. 003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P =. 047; log-rank P =. 04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P <. 001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P =. 02; log-rank P
- Published
- 2022
15. CD28.OX40 co-stimulatory combination is high associated activity with of CAR.CD30 long in vivoT persistence cells and
- Author
-
Guercio, M., Orlando, D., Cecca, S. D., Sinibaldi, M., Boffa, I., Caruso, S., Abbaszadeh, Z., Camera, A., Cembrola, B., Bovetti, K., Manni, S., Caruana, I., Ciccone, R., Bufalo, F. D., Merli, P., Vinti, L., Girardi, K., Ruggeri, A., de Stefanis, C., Pezzullo, M., Giorda, E., Scarsella, M., de Vito, R., Barresi, S., Ciolfi, A., Tartaglia, M., Moretta, L., Locatelli, Franco, Quintarelli, C., and de Angelis, B.
- Subjects
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,CAR.CD30 - Published
- 2021
16. Oncolytic adenovirus and gene therapy with EphA2-BiTE for the treatment of pediatric high-grade gliomas
- Author
-
Arnone, C. M., Polito, V. A., Mastronuzzi, A., Carai, A., Diomedi, F. C., Antonucci, L., Petrilli, L. L., Vinci, M., Ferrari, F., Salviato, E., Scarsella, M., De Stefanis, C., Weber, G., Quintarelli, C., De Angelis, B., Brenner, M. K., Gottschalk, S., Hoyos, V., Locatelli, Franco, Caruana, I., Del Bufalo, F., Locatelli F. (ORCID:0000-0002-7976-3654), Arnone, C. M., Polito, V. A., Mastronuzzi, A., Carai, A., Diomedi, F. C., Antonucci, L., Petrilli, L. L., Vinci, M., Ferrari, F., Salviato, E., Scarsella, M., De Stefanis, C., Weber, G., Quintarelli, C., De Angelis, B., Brenner, M. K., Gottschalk, S., Hoyos, V., Locatelli, Franco, Caruana, I., Del Bufalo, F., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background Pediatric high-grade gliomas (pHGGs) are among the most common and incurable malignant neoplasms of childhood. Despite aggressive, multimodal treatment, the outcome of children with high-grade gliomas has not significantly improved over the past decades, prompting the development of innovative approaches. Methods To develop an effective treatment, we aimed at improving the suboptimal antitumor efficacy of oncolytic adenoviruses (OAs) by testing the combination with a gene-Therapy approach using a bispecific T-cell engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2), conveyed by a replication-incompetent adenoviral vector (EphA2 adenovirus (EAd)). The combinatorial approach was tested in vitro, in vivo and thoroughly characterized at a molecular level. Results After confirming the relevance of EphA2 as target in pHGGs, documenting a significant correlation with worse clinical outcome of the patients, we showed that the proposed strategy provides significant EphA2-BiTE amplification and enhanced tumor cell apoptosis, on coculture with T cells. Moreover, T-cell activation through an agonistic anti-CD28 antibody further increased the activation/proliferation profiles and functional response against infected tumor cells, inducing eradication of highly resistant, primary pHGG cells. The gene-expression analysis of tumor cells and T cells, after coculture, revealed the importance of both EphA2-BiTE and costimulation in the proposed system. These in vitro observations translated into significant tumor control in vivo, in both subcutaneous and a more challenging orthotopic model. Conclusions The combination of OA and EphA2-BiTE gene therapy strongly enhances the antitumor activity of OA, inducing the eradication of highly resistant tumor cells, thus supporting the clinical translation of the approach.
- Published
- 2021
17. Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling
- Author
-
Nazio, F., Po, A., Abballe, L., Ballabio, C., Diomedi Camassei, F., Bordi, Matteo, Camera, A., Caruso, S., Caruana, I., Pezzullo, M., Ferraina, C., Milletti, G., Gianesello, M., Reddel, S., De Luca, C. D., Ceglie, D., Marinelli, S., Campello, S., Papaleo, E., Miele, E., Cacchione, A., Carai, A., Vinci, M., Velardi, E., De Angelis, B., Tiberi, L., Quintarelli, C., Mastronuzzi, A., Ferretti, E., Locatelli, Franco, Cecconi, Francesco, Bordi M. (ORCID:0000-0001-8207-8546), Locatelli F. (ORCID:0000-0002-7976-3654), Cecconi F. (ORCID:0000-0002-5614-4359), Nazio, F., Po, A., Abballe, L., Ballabio, C., Diomedi Camassei, F., Bordi, Matteo, Camera, A., Caruso, S., Caruana, I., Pezzullo, M., Ferraina, C., Milletti, G., Gianesello, M., Reddel, S., De Luca, C. D., Ceglie, D., Marinelli, S., Campello, S., Papaleo, E., Miele, E., Cacchione, A., Carai, A., Vinci, M., Velardi, E., De Angelis, B., Tiberi, L., Quintarelli, C., Mastronuzzi, A., Ferretti, E., Locatelli, Franco, Cecconi, Francesco, Bordi M. (ORCID:0000-0001-8207-8546), Locatelli F. (ORCID:0000-0002-7976-3654), and Cecconi F. (ORCID:0000-0002-5614-4359)
- Abstract
Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MBGroup3) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MBGroup3 stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MBGroup3 stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MBGroup3 outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MBGroup3.
- Published
- 2021
18. Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts
- Author
-
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
19. Inclusion of the Inducible Caspase 9 Suicide Gene in CAR Construct Increases Safety of CAR.CD19 T Cell Therapy in B-Cell Malignancies
- Author
-
Guercio, M., Manni, S., Boffa, I., Caruso, S., Di Cecca, S., Sinibaldi, M., Abbaszadeh, Z., Camera, A., Ciccone, R., Polito, V. A., Ferrandino, F., Reddel, S., Catanoso, M. L., Bocceri, E., Del Bufalo, F., Algeri, M., De Angelis, B., Quintarelli, C., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Guercio, M., Manni, S., Boffa, I., Caruso, S., Di Cecca, S., Sinibaldi, M., Abbaszadeh, Z., Camera, A., Ciccone, R., Polito, V. A., Ferrandino, F., Reddel, S., Catanoso, M. L., Bocceri, E., Del Bufalo, F., Algeri, M., De Angelis, B., Quintarelli, C., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
T cells engineered with chimeric antigen receptor (CAR-T cells) are an effective treatment in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia or B-cell non-Hodgkin lymphoma. Despite the reported exciting clinical results, the CAR-T cell approach needs efforts to improve the safety profile, limiting the occurrence of adverse events in patients given this treatment. Besides the most common side effects, such as cytokine release syndrome and CAR-T cell–related encephalopathy syndrome, another potential issue involves the inadvertent transduction of leukemia B cells with the CAR construct during the manufacturing process, thus leading to the possibility of a peculiar mechanism of antigen masking and treatment resistance. In this study, we investigated whether the inclusion of the inducible caspase 9 (iC9) suicide gene in the CAR construct design could be an effective safety switch to control malignant CAR+ B cells, ultimately counteracting this serious adverse event. iC9 is a suicide gene able to be activated through binding with an otherwise inert small biomolecule, known as AP1903. The exposure of iC9.CAR.CD19-DAUDI lymphoma and iC9.CAR.CD19-NALM-6 leukemia cells in vitro to 20 nM of AP1903 resulted into the prompt elimination of CAR+ B-leukemia/lymphoma cell lines. The results obtained in the animal model corroborate in vitro data, since iC9.CAR.CD19+ tumor cells were controlled in vivo by the activation of the suicide gene through administration of AP1903. Altogether, our data indicate that the inclusion of the iC9 suicide gene may result in a safe CAR-T cell product, even when manufacturing starts from biological materials characterized by heavy leukemia blast contamination.
- Published
- 2021
20. SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best
- Author
-
Salinas, A. F., Mortari, E. P., Terreri, S., Quintarelli, C., Pulvirenti, F., Di Cecca, S., Guercio, M., Milito, C., Bonanni, L., Auria, S., Romaggioli, L., Cusano, G., Albano, C., Zaffina, S., Perno, C. F., Spadaro, G., Locatelli, Franco, Carsetti, R., Quinti, I., Locatelli F. (ORCID:0000-0002-7976-3654), Salinas, A. F., Mortari, E. P., Terreri, S., Quintarelli, C., Pulvirenti, F., Di Cecca, S., Guercio, M., Milito, C., Bonanni, L., Auria, S., Romaggioli, L., Cusano, G., Albano, C., Zaffina, S., Perno, C. F., Spadaro, G., Locatelli, Franco, Carsetti, R., Quinti, I., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. Methods: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. Results: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. Conclusion: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.
- Published
- 2021
21. B cell response induced by SARS-CoV-2 infection is boosted by the BNT162b2 vaccine in primary antibody deficiencies
- Author
-
Pulvirenti, F., Salinas, A. F., Milito, C., Terreri, S., Mortari, E. P., Quintarelli, C., Di Cecca, S., Lagnese, G., Punziano, A., Guercio, M., Bonanni, L., Auria, S., Villani, F., Albano, C., Locatelli, Franco, Spadaro, G., Carsetti, R., Quinti, I., Locatelli F. (ORCID:0000-0002-7976-3654), Pulvirenti, F., Salinas, A. F., Milito, C., Terreri, S., Mortari, E. P., Quintarelli, C., Di Cecca, S., Lagnese, G., Punziano, A., Guercio, M., Bonanni, L., Auria, S., Villani, F., Albano, C., Locatelli, Franco, Spadaro, G., Carsetti, R., Quinti, I., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Patients with primary antibody deficiencies are at risk in the current COVID-19 pandemic due to their impaired response to infection and vaccination. Specifically, patients with common variable immunodeficiency (CVID) generated poor spike-specific antibody and T cell responses after immunization. Methods: Thirty-four CVID convalescent patients after SARS-CoV-2 infection, 38 CVID patients immunized with two doses of the BNT162b2 vaccine, and 20 SARS-CoV-2 CVID convalescents later and immunized with BNT162b2 were analyzed for the anti-spike IgG production and the generation of spike-specific memory B cells and T cells. Results: Spike-specific IgG was induced more frequently after infection than after vaccination (82% vs. 34%). The antibody response was boosted in convalescents by vaccination. Although immunized patients generated atypical memory B cells possibly by extra-follicular or incomplete germinal center reactions, convalescents responded to infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Poor spike-specific T cell responses were measured independently from the immunological challenge. Conclusions: SARS-CoV-2 infection primed a more efficient classical memory B cell response, whereas the BNT162b2 vaccine induced non-canonical B cell responses in CVID. Natural infection responses were boosted by subsequent immunization, suggesting the possibility to further stimulate the immune response by additional vaccine doses in CVID.
- Published
- 2021
22. Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma
- Author
-
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
23. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety
- Author
-
Hoyos, V, Savoldo, B, Quintarelli, C, Mahendravada, A, Zhang, M, Vera, J, Heslop, H E, Rooney, C M, Brenner, M K, and Dotti, G
- Published
- 2010
- Full Text
- View/download PDF
24. The immune system of children: the key to understanding SARS-CoV-2 susceptibility?
- Author
-
Carsetti, R., Quintarelli, C., Quinti, I., Piano Mortari, E., Zumla, A., Ippolito, G., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Carsetti, R., Quintarelli, C., Quinti, I., Piano Mortari, E., Zumla, A., Ippolito, G., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
no abstract available
- Published
- 2020
25. NK cells as adoptive cellular therapy for hematological malignancies: Advantages and hurdles
- Author
-
Caruso, S., De Angelis, B., Carlomagno, S., Del Bufalo, F., Sivori, S., Locatelli, Franco, Quintarelli, C., Locatelli F. (ORCID:0000-0002-7976-3654), Caruso, S., De Angelis, B., Carlomagno, S., Del Bufalo, F., Sivori, S., Locatelli, Franco, Quintarelli, C., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Natural killer cells are an essential component of the innate immune system and play a crucial role in immunity against malignancies, without, at difference with T cells, requiring antigen priming or inducing graft-versus-host-disease. Hence, Natural Killer cells can provide a valuable source of allogeneic “off-the-shelf” adoptive therapy and mediate major antileukemia effects, without inducing potentially lethal alloreactivity. Several cell sources have been used for producing and expanding large numbers of clinical-grade natural killer cells. In this review, we will discuss the advantages and challenges of Natural Killer cell-based therapeutic approaches for hematological malignancies, also exploring different strategies to potentiate their clinical application.
- Published
- 2020
26. Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia
- Author
-
Quintarelli, C., Sivori, S., Caruso, S., Carlomagno, S., Falco, M., Boffa, I., Orlando, D., Guercio, M., Abbaszadeh, Z., Sinibaldi, M., Di Cecca, S., Camera, A., Cembrola, B., Pitisci, A., Andreani, M., Vinti, L., Gattari, S., Del Bufalo, F., Algeri, M., Li Pira, G., Moseley, A., De Angelis, B., Moretta, L., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Quintarelli, C., Sivori, S., Caruso, S., Carlomagno, S., Falco, M., Boffa, I., Orlando, D., Guercio, M., Abbaszadeh, Z., Sinibaldi, M., Di Cecca, S., Camera, A., Cembrola, B., Pitisci, A., Andreani, M., Vinti, L., Gattari, S., Del Bufalo, F., Algeri, M., Li Pira, G., Moseley, A., De Angelis, B., Moretta, L., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently transduced by a retroviral vector, carrying a second-generation CAR targeting CD19. CAR expression was demonstrated across the different NK-cell subsets. CAR.CD19-NK cells display higher antileukemic activity toward CD19+ cell lines and primary blasts obtained from patients with B-cell precursor ALL compared with unmodified NK cells. In vivo animal model data showed that the antileukemia activity of CAR.CD19-NK cell is superimposable to that of CAR-T cells, with a lower xenograft toxicity profile. These data support the feasibility of generating feeder-free expanded, genetically modified peripheral blood NK cells for effective “off-the-shelf” immuno-gene-therapy, while their innate alloreactivity can be safely harnessed to potentiate allogeneic cell therapy.
- Published
- 2020
27. Stimuli-responsive nanoparticle-assisted immunotherapy: A new weapon against solid tumours
- Author
-
De Angelis, B., Depalo, N., Petronella, F., Quintarelli, C., Curri, M. L., Pani, R., Calogero, A., Locatelli, Franco, De Sio, L., Locatelli F. (ORCID:0000-0002-7976-3654), De Angelis, B., Depalo, N., Petronella, F., Quintarelli, C., Curri, M. L., Pani, R., Calogero, A., Locatelli, Franco, De Sio, L., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Although significant improvements in cancer treatment have led to a longer survival period, the death rate of patients with solid tumours has not changed during the last decades. Most researchers are currently concentrating on defining the mechanisms of the different resistance pathways activated by tumour cells; meanwhile, the role of limited drug distribution within tumours has been neglected. The application of nanotechnology in medicine offers unexplored opportunities for realizing a new generation of anticancer therapies that can overcome the physical hindrances that characterize solid tumours. Indeed, surface-engineered nanoparticles (NPs) (both organic and inorganic) have been used as powerful tools in cancer therapy. Particularly, Au NPs have been utilized to develop a new drug-free treatment, photo-thermal therapy (PTT), due to their stimuli-responsive properties. PTT combined with immunotherapy represents a major breakthrough in the fight against malignant solid tumours. In this review, we provide a complete overview of the synergistic approaches based on PTT and immunotherapy, considering the selection, design, and functionalization of the NPs and their thermo-optical properties, moving to in vivo studies and finally to clinical trial applications in patients suffering from solid tumours.
- Published
- 2020
28. Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases
- Author
-
Carsetti, R., Zaffina, S., Piano Mortari, E., Terreri, S., Corrente, F., Capponi, C., Palomba, P., Mirabella, M., Cascioli, S., Palange, P., Cuccaro, I., Milito, C., Zumla, A., Maeurer, M., Camisa, V., Vinci, M. R., Santoro, A., Cimini, E., Marchioni, L., Nicastri, E., Palmieri, F., Agrati, C., Ippolito, G., Porzio, O., Concato, C., Onetti Muda, A., Raponi, M., Quintarelli, C., Quinti, I., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Carsetti, R., Zaffina, S., Piano Mortari, E., Terreri, S., Corrente, F., Capponi, C., Palomba, P., Mirabella, M., Cascioli, S., Palange, P., Cuccaro, I., Milito, C., Zumla, A., Maeurer, M., Camisa, V., Vinci, M. R., Santoro, A., Cimini, E., Marchioni, L., Nicastri, E., Palmieri, F., Agrati, C., Ippolito, G., Porzio, O., Concato, C., Onetti Muda, A., Raponi, M., Quintarelli, C., Quinti, I., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; eight patients with Mild COVID-19 disease and eight cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated with asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.
- Published
- 2020
29. Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia
- Author
-
Pane, F, Cimino, G, Izzo, B, Camera, A, Vitale, A, Quintarelli, C, Picardi, M, Specchia, G, Mancini, M, Cuneo, A, Mecucci, C, Martinelli, G, Saglio, G, Rotoli, B, Mandelli, F, Salvatore, F, and Foà, R
- Published
- 2005
- Full Text
- View/download PDF
30. Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia
- Author
-
Quintarelli, C., primary, Sivori, S., additional, Caruso, S., additional, Carlomagno, S., additional, Falco, M., additional, Boffa, I., additional, Orlando, D., additional, Guercio, M., additional, Abbaszadeh, Z., additional, Sinibaldi, M., additional, Di Cecca, S., additional, Camera, A., additional, Cembrola, B., additional, Pitisci, A., additional, Andreani, M., additional, Vinti, L., additional, Gattari, S., additional, Del Bufalo, F., additional, Algeri, M., additional, Li Pira, G., additional, Moseley, A., additional, De Angelis, B., additional, Moretta, L., additional, and Locatelli, F., additional
- Published
- 2019
- Full Text
- View/download PDF
31. Human CAR NK cells: A new non-viral method allowing high efficient transfection and strong tumor cell killing
- Author
-
Ingegnere, T., Mariotti, F. R., Pelosi, A., Quintarelli, C., De Angelis, B., Tumino, N., Besi, F., Cantoni, C., Locatelli, Franco, Vacca, P., Moretta, L., Locatelli F. (ORCID:0000-0002-7976-3654), Ingegnere, T., Mariotti, F. R., Pelosi, A., Quintarelli, C., De Angelis, B., Tumino, N., Besi, F., Cantoni, C., Locatelli, Franco, Vacca, P., Moretta, L., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
CAR-NK cells may represent a valuable tool, complementary to CART cells, in adoptive immunotherapy of leukemia and solid tumors. However, gene transfer to human NK cells is a challenging task, particularly with non-virus-based techniques. Here, we describe a new procedure allowing efficient electroporation-based transfection of plasmid DNA, including CAR and CCR7 genes, in resting or cytokine-expanded human NK cell populations and NK-92 cell line. This procedure may offer a suitable platform for a safe and effective use of CAR-NK cells in adoptive immunotherapy of cancer.
- Published
- 2019
32. Effect of oral defibrotide on tissue-plasminogen activator and tissue-plasminogen activator inhibitor balance
- Author
-
Violi, F., Ferro, D., Saliola, M., Quintarelli, C., Basili, S., and Balsano, F.
- Published
- 1992
- Full Text
- View/download PDF
33. 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
-
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
34. MicroRNAs in neuroblastoma: Biomarkers with therapeutic potential
- Author
-
Galardi, A., Colletti, M., Businaro, P., Quintarelli, C., Locatelli, Franco, Di Giannatale, A., Locatelli F. (ORCID:0000-0002-7976-3654), Galardi, A., Colletti, M., Businaro, P., Quintarelli, C., Locatelli, Franco, Di Giannatale, A., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Neuroblastoma is the most common extracranial solid tumor in infancy. The majority of children have a disseminated disease at diagnosis with bone marrow as the most common site of metastasis. Although several prognostic factors have been defined (i.e. age, stage, histology, recurrent genetic anomalies), the identification of non-invasive biomarkers for disease follow-up and therapy monitoring is indeed still a clinical need. Aberrant regulation of microRNAs (miRNAs) expression has been implicated in several malignancies. Objectives: In this mini-review, we describe the recent findings about miRNAs in neuroblastoma, both in the tumor and circulation, with particular focus on those involved in tumor progression and drug resistance. Furthermore, we will discuss the use of specific miRNAs as potential therapeutic tools in this tumor. Results: Several miRNAs have been identified to be down- or up-regulated in primary tumors and have been associated with MYCN amplification, differentiation, dissemination and chemoresistance. Little evidence is available in the literature about circulating miRNAs which are of particular interest as potential biomarkers for liquid biopsy. Conclusion: Identification of body-fluid markers for non-invasive diagnosis, risk tratification, treatment monitoring and tumor follow-up, is gaining growing interest, especially in the pediatric field. miRNAs are suitable candidates as biomarkers in neuroblastoma but further investigations are needed to expand knowledge regarding their role in this malignancy to design specific approaches of miRNAs-mediated therapies.
- Published
- 2018
35. Adoptive immunotherapy using prame-specific t cells in medulloblastoma
- Author
-
Orlando, D., Miele, E., De Angelis, B., Guercio, M., Boffa, I., Sinibaldi, M., Po, A., Caruana, I., Abballe, L., Carai, A., Caruso, S., Camera, A., Moseley, A., Hagedoorn, R. S., Heemskerk, M. H. M., Giangaspero, F., Mastronuzzi, A., Ferretti, E., Locatelli, Franco, Quintarelli, C., Locatelli F. (ORCID:0000-0002-7976-3654), Orlando, D., Miele, E., De Angelis, B., Guercio, M., Boffa, I., Sinibaldi, M., Po, A., Caruana, I., Abballe, L., Carai, A., Caruso, S., Camera, A., Moseley, A., Hagedoorn, R. S., Heemskerk, M. H. M., Giangaspero, F., Mastronuzzi, A., Ferretti, E., Locatelli, Franco, Quintarelli, C., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A-02+ DAOY cells as well as primary HLA-A-02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell- related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A-02+ medulloblastoma. Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells.
- Published
- 2018
36. Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma
- Author
-
Quintarelli, C., Orlando, D., Boffa, I., Guercio, M., Polito, V. A., Petretto, A., Lavarello, C., Sinibaldi, M., Weber, G., Del Bufalo, F., Giorda, E., Scarsella, M., Petrini, S., Pagliara, D., Locatelli, Franco, De Angelis, B., Caruana, I., Locatelli F. (ORCID:0000-0002-7976-3654), Quintarelli, C., Orlando, D., Boffa, I., Guercio, M., Polito, V. A., Petretto, A., Lavarello, C., Sinibaldi, M., Weber, G., Del Bufalo, F., Giorda, E., Scarsella, M., Petrini, S., Pagliara, D., Locatelli, Franco, De Angelis, B., Caruana, I., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Chimeric antigen receptor (CAR) T-cell therapy has been shown to be dramatically effective in the treatment of B-cell malignancies. However, there are still substantial obstacles to overcome, before similar responses can be achieved in patients with solid tumors. We evaluated both in vitro and in a preclinical murine model the efficacy of different 2nd and 3rd generation CAR constructs targeting GD2, a disial-ganglioside expressed on the surface of neuroblastoma (NB) tumor cells. In order to address potential safety concerns regarding clinical application, an inducible safety switch, namely inducible Caspase-9 (iC9), was also included in the vector constructs. Our data indicate that a 3rd generation CAR incorporating CD28.4-1BB costimulatory domains is associated with improved anti-tumor efficacy as compared with a CAR incorporating the combination of CD28.OX40 domains. We demonstrate that the choice of 4-1BB signaling results into significant amelioration of several CAR T-cell characteristics, including: 1) T-cell exhaustion, 2) basal T-cell activation, 3) in vivo tumor control and 4) T-cell persistence. The fine-tuning of T-cell culture conditions obtained using IL7 and IL15 was found to be synergic with the CAR.GD2 design in increasing the anti-tumor activity of CAR T cells. We also demonstrate that activation of the suicide gene iC9, included in our construct without significantly impairing neither CAR expression nor anti-tumor activity, leads to a prompt induction of apoptosis of GD2.CAR T cells. Altogether, these findings are instrumental in optimizing the function of CAR T-cell products to be employed in the treatment of children with NB.
- Published
- 2018
37. The EURE-CART project as a prototype model for CAR T-cell immunotherapy in Europe
- Author
-
Locatelli, Franco, Quintarelli, C., Locatelli F. (ORCID:0000-0002-7976-3654), Locatelli, Franco, Quintarelli, C., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
NO ABSTRACT
- Published
- 2018
38. Relation between Lupus Anticoagulant and Splanchnic Venous Thrombosis in Cirrhosis of the Liver.
- Author
-
Violi, F, Ferro, D, Basili, S, D'Angelo, A, Mazzola, G, Quintarelli, C, and Cordova, C.
- Published
- 1994
39. Molecular monitoring in chronic myeloid leukemia (CML)
- Author
-
Izzo B., Accetta R., Caruso S., De Angelis B., Del Prete C., Errichiello S., Galdiero A., Casadei G. M., Musella F., Quintarelli C., Visconti R., Pane F., Izzo, B., Accetta, R., Caruso, S., De Angelis, B., Del Prete, C., Errichiello, S., Galdiero, A., Casadei, G. M., Musella, F., Quintarelli, C., Visconti, R., and Pane, F.
- Abstract
The pathognomonic genetic alteration in CML is the formation of the BCR-ABL fusion gene, which produces a constitutively active tyrosine kinase that drives leukemic transformation. Targeted tyrosine kinase inhibitor treatment is the cornerstone of modern therapy for this hematologic malignancy. Analysis of BCR-ABL [through reverse transcriptase-quantitative polymerase chain reaction (RT-QPCR)] is the gold standard approach for quantitatively assessing minimal residual disease and monitoring the efficacy of tyrosine kinase inhibitor therapy in CML patients. The continuous therapeutic improvement has led to increasingly ambitious treatment endpoints, which, in turn, require more and more refined measurement and definition of molecular response levels. For these reasons standardization efforts of monitoring by RT-QPCR are now focused on ensuring reliable and harmonized expression of quantitative results.
- Published
- 2015
40. Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma
- Author
-
Rigo, V., Emionite, L., Daga, A., Astigiano, S., Corrias, M. V., Quintarelli, C., Locatelli, Franco, Ferrini, S., Croce, M., Locatelli F. (ORCID:0000-0002-7976-3654), Rigo, V., Emionite, L., Daga, A., Astigiano, S., Corrias, M. V., Quintarelli, C., Locatelli, Franco, Ferrini, S., Croce, M., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Anti-PD-1 or anti-PD-L1 blocking monoclonal antibodies (mAbs) have shown potent anti-tumor effects in adult cancer patients and clinical studies have recently been started in pediatric cancers, including high-risk/relapsing neuroblastoma (NB). Therefore, we studied the effects of anti-PD-1/PD-L1 mAbs in two syngeneic models of disseminated NB generated by the injection of either Neuro2a or NXS2 cells, which express PD-L1. In addition, we tested the combination of these agents with the immune-enhancing cytokine IL-21, the Ecto-NTPDase inhibitor POM-1, an anti-CD25 mAb targeting Treg cells, or an anti-CD4 mAb. We previously showed that CD4-transient depletion removes CD4+CD25+ Treg cells and other CD4+CD25- regulatory subsets. Here we show that mono-therapy with anti-PD-1/PD-L1 mAbs had no effect on systemic NB progression in vivo, and also their combination with IL-21, POM-1 or anti-CD25 mAb was ineffective. The combined use of anti-PD-1 with an anti-CD4 mAb mediated a very potent, CD8-dependent, synergistic effect leading to significant elongation of tumor-free survival of mice, complete tumor regression and durable anti-NB immunity. Similar results were obtained by combining the anti-PD-L1 and anti-CD4 mAbs. These findings indicate that both PD-1/PD-L1 and CD4+ T cell-related immune-regulatory mechanisms must be simultaneously blocked to mediate therapeutic effects in these models.
- Published
- 2017
41. ADOPTIVE CELL IMMUNOTHERAPY IN MEDULLOBLASTOMA BASED ON T CELLS REDIRECTED TOWARD TUMOR CELLS BY PRAME SPECIFIC alpha beta TCR GENE MODIFICATION
- Author
-
Caruana, I., Orlando, D., Angelis, B. de, Boffa, I., Guercio, M., Carai, A., Massimi, L., Ferretti, E., Miele, E., Po, A., Moseley, A., Hagedoorn, R.S., Boer, R. de, Falkenburg, J.H.F., Heemskerk, M.H.M., Locatelli, F., Mastronuzzi, A., and Quintarelli, C.
- Published
- 2016
42. Identification of Annexin A1 interacting proteins in chronic myeloid leukemia KCL22 cells
- Author
-
Colavita I, Esposito N, Quintarelli C, Nigro E, Pane F, Ruoppolo M, Salvatore F., Colavita, I, Esposito, N, Quintarelli, C, Nigro, E, Pane, F, Ruoppolo, M, and Salvatore, F.
- Published
- 2013
43. MOLECULAR EVALUATION OF ZNF224 MRNA EXPRESSION IN CML PATIENTS AS A NOVEL DETERMINANT OF TKI RESPONSIVENESS
- Author
-
Errichiello, S., Caruso, S., BIAGIO DE ANGELIS, Quintarelli, C., Pisano, I., Izzo, B., Muccioli, G., Musella, F., Del Prete, C., Visconti, R., Galdiero, A., Cacciapuoti, V., Siciliano, M., Pugliese, N., Della Pepa, R., Pane, F., Errichiello, Santa, Caruso, Simona, DE ANGELIS, Biagio, Quintarelli, Concetta, Pisano, Ida, Izzo, Barbara, G., Muccioli, F., Musella, C. Del, Prete, R., Visconti, A., Galdiero, V., Cacciapuoti, M., Siciliano, Pugliese, Novella, DELLA PEPA, Roberta, and Pane, Fabrizio
- Abstract
The transcription factor Wilms’ tumor gene 1, WT1, is implicated both in normal developmental processes and in the generation of a variety of solid tumors and hematological malignancies. WT1 is highly expressed in leukemia cells and its overexpression is associated with a poor response to therapy. Recently the Krüppel-like zinc-finger protein, ZNF224 was identified as a novel WT1-interacting factor involved in WT1 transcriptional regulation. ZNF224 itself could be modulated by cytosine arabinoside (ara-C), a drug widely used in the treatment of myeloid leukemia and that ZNF224 overexpression increases susceptibility to apoptosis of Ph+ K562 cell lines. In our retrospective analysis we evaluated the relative expression of ZNF224 mRNA in 30 adult patients with BCR-ABL–positive chronic phase chronic myeloid leukaemia (CP-CML) as a determinant of imatinib sensitivity. Methods: Response to tyrosine kinase inhibitor (TKI) imatinib is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. Response to the therapy was classified as optimal, warning, and failure, according to the recent ELN criteria. We compared the ZNF224 expression at diagnosis with molecular response over the first 12 month of imatinib therapy. Sample have been selected, for retrospective analysis, for them interim molecular results a 12 month, showing 15 patients in optimal response (OR), 10 patients in a warning response (WR) and 5 patients in failure response (FR). 5 healthy donors (HDs) were included to the study. All patients signed informed consent in accordance with the Declaration of Helsinki. RT-qPCR results were normalized by the expression of ABL mRNA (Normalized mRNA copy Number: NCN).Results:ZNF224 mRNA were significantly up-regulated in PB samples at diagnosis of patients with OR compared to patients with WR/FR, (1.13±0.76 vs 0.62±0.25 NCN,respectively; p=0.05). Interesting the ZNF224 mRNA expression in HDs was significantly higher (2.11±0.98 NCN vs OR patients, p=0.05 and WR/FR patients; p=0.0005). The treatment for 12 month with imatinib increase the ZNF224 expression in both CML categories (2.91±1.72 NCN in OR and1.77±1.52 NCN in WR/FR; p=0.05). Conclusions:We observed that the OR patients express a significantly higher number of copies of the ZNF224 transcript than WR/FR. Furthermore, in both groups of patients at diagnosis, ZNF224 protein levels are lower than those after therapy with TKI at 12 months
- Published
- 2015
44. Overcoming challenges in CAR T-cell product CGMP release
- Author
-
Quintarelli, C., Locatelli, Franco, Caruana, I., De Angelis, B., Locatelli F. (ORCID:0000-0002-7976-3654), Quintarelli, C., Locatelli, Franco, Caruana, I., De Angelis, B., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
NO ABSTRACT
- Published
- 2016
45. Advanced-stage Hodgkin Lymphoma: US/Chest Radiography for Detection of Relapse in Patients in First Complete Remission - A Randomized Trial of Routine Surveillance Imaging Procedures
- Author
-
Picardi, M, Pugliese, N, Cirillo, M, Zeppa, P, Cozzolino, I, Ciancia, G, Pettinato, G, Salvatore, Claudia, Quintarelli, C, and Pane, F.
- Published
- 2014
46. Reduced Expression Level of SHP1 Gives An Additive Survival Advantage to the Ph plus Cells of Chronic Myeloid Leukemia (CML) Patients and Provides a Novel Pretreatment Predictor of Major Molecular Response Achievement in CML Patients
- Author
-
Esposito, N, Quintarelli, C, Colavita, I, Izzo, B, Peluso, AL, Ruoppolo, M, Del Vecchio, L, Russo, D, Branford, S, Iacobucci, I, Thornquist, M, Barnett, M, Melo, J, Saglio, G, Radich, J, Peter, L, Martinelli, G, Kalebic, T, Hughes, T, and Pane, F
- Published
- 2010
47. Il paesaggio rurale dell’Alto Mugello: un approccio multidisciplinare per la sua conservazione
- Author
-
Fagarazzi, C., Franciosi, C., and Quintarelli, C.
- Subjects
valutazione del paesaggio - Published
- 2006
48. Significant reduction of the hybrid BCR/ABL transcripts after inducyion and consolidation therapy is a powerful predictor of tratmnt response in adult Philadelphia-positive acute lymbophoblastic leukemia
- Author
-
Pane F, Cimino G, Izzo B, Camera A, Vitale A, Quintarelli C, Picardi M, Specchia G, Mancini M, Cuneo A, Mecucci C, Martinelli G, Saglio G, Rotoli B, Mandelli F, Salvatore F, Foa R, and Gimema Group
- Published
- 2005
49. Decitabine up-regulates the expression of the cancer-associate prame antigen in early chronic phase CML cells
- Author
-
Pane, F, Quintarelli, C, Izzo, B, Martinelli, G, Intrieri, Mariano, Luciano, L, Amabile, M, Rosti, G, Saglio, G, Baccarani, M, Salvatore, F., Pane, Fabrizio, Quintarelli, Concetta, Izzo, Barbara, Martinelli, G., Intrieri, M., Luciano, L., Amabile, M., Rosti, G., Saglio, G., Baccarani, M., and Salvatore, F.
- Published
- 2003
50. Decitabine up-regulates the expression of the cancer-associate prame antigen in early chronic phase
- Author
-
Pane, F, Quintarelli, C, Izzo, B, Martinelli, G, Intrieri, Mariano, Luciano, L, Amabile, M, Rosti, G, Saglio, G, Baccarani, M, and Salvatore, F.
- Published
- 2003
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.