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Your search keyword '"Tettamanti S."' showing total 3 results
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3 results on '"Tettamanti S."'

1. Targeting CD33 in Chemoresistant AML Patient-Derived Xenografts by CAR-CIK Cells Modified with an Improved SB Transposon System

Author

Rotiroti, M, Buracchi, C, Arcangeli, S, Galimberti, S, Valsecchi, M, Perriello, V, Rasko, T, Alberti, G, Magnani, C, Cappuzzello, C, Lundberg, F, Pande, A, Dastoli, G, Introna, M, Serafini, M, Biagi, E, Izsvák, Z, Biondi, A, Tettamanti, S, Rotiroti, Maria Caterina, Buracchi, Chiara, Arcangeli, Silvia, Galimberti, Stefania, Valsecchi, Maria Grazia, Perriello, Vincenzo Maria, Rasko, Tamas, Alberti, Gaia, Magnani, Chiara Francesca, Cappuzzello, Claudia, Lundberg, Felix, Pande, Amit, Dastoli, Giuseppe, Introna, Martino, Serafini, Marta, Biagi, Ettore, Izsvák, Zsuzsanna, Biondi, Andrea, Tettamanti, Sarah, Rotiroti, M, Buracchi, C, Arcangeli, S, Galimberti, S, Valsecchi, M, Perriello, V, Rasko, T, Alberti, G, Magnani, C, Cappuzzello, C, Lundberg, F, Pande, A, Dastoli, G, Introna, M, Serafini, M, Biagi, E, Izsvák, Z, Biondi, A, Tettamanti, S, Rotiroti, Maria Caterina, Buracchi, Chiara, Arcangeli, Silvia, Galimberti, Stefania, Valsecchi, Maria Grazia, Perriello, Vincenzo Maria, Rasko, Tamas, Alberti, Gaia, Magnani, Chiara Francesca, Cappuzzello, Claudia, Lundberg, Felix, Pande, Amit, Dastoli, Giuseppe, Introna, Martino, Serafini, Marta, Biagi, Ettore, Izsvák, Zsuzsanna, Biondi, Andrea, and Tettamanti, Sarah

Abstract

The successful implementation of chimeric antigen receptor (CAR)-T cell therapy in the clinical context of B cell malignancies has paved the way for further development in the more critical setting of acute myeloid leukemia (AML). Among the potentially targetable AML antigens, CD33 is insofar one of the main validated molecules. Here, we describe the feasibility of engineering cytokine-induced killer (CIK) cells with a CD33.CAR by using the latest optimized version of the non-viral Sleeping Beauty (SB) transposon system "SB100X-pT4." This offers the advantage of improving CAR expression on CIK cells, while reducing the amount of DNA transposase as compared to the previously employed "SB11-pT" version. SB-modified CD33.CAR-CIK cells exhibited significant antileukemic activity in vitro and in vivo in patient-derived AML xenograft models, reducing AML development when administered as an "early treatment" and delaying AML progression in mice with established disease. Notably, by exploiting an already optimized xenograft chemotherapy model that mimics human induction therapy in mice, we demonstrated for the first time that CD33.CAR-CIK cells are also effective toward chemotherapy resistant/residual AML cells, further supporting its future clinical development and implementation within the current standard regimens.

Published
2020

2. Targeting CD33 in Chemoresistant AML Patient-Derived Xenografts by CAR-CIK Cells Modified with an Improved SB Transposon System.

Author

Rotiroti MC, Buracchi C, Arcangeli S, Galimberti S, Valsecchi MG, Perriello VM, Rasko T, Alberti G, Magnani CF, Cappuzzello C, Lundberg F, Pande A, Dastoli G, Introna M, Serafini M, Biagi E, Izsvák Z, Biondi A, and Tettamanti S

Subjects
Animals, Feasibility Studies, Gene Transfer Techniques, Humans, Mice, Mice, Inbred NOD, Mice, SCID, THP-1 Cells, Transposases genetics, Transposases metabolism, Treatment Outcome, Xenograft Model Antitumor Assays, Cell Engineering methods, Cell Transplantation methods, Cytokine-Induced Killer Cells immunology, Drug Resistance, Neoplasm, Genetic Therapy methods, Heterografts, Immunotherapy, Adoptive methods, Leukemia, Experimental therapy, Leukemia, Myeloid, Acute therapy, Receptors, Chimeric Antigen genetics, Sialic Acid Binding Ig-like Lectin 3 genetics
Abstract

The successful implementation of chimeric antigen receptor (CAR)-T cell therapy in the clinical context of B cell malignancies has paved the way for further development in the more critical setting of acute myeloid leukemia (AML). Among the potentially targetable AML antigens, CD33 is insofar one of the main validated molecules. Here, we describe the feasibility of engineering cytokine-induced killer (CIK) cells with a CD33.CAR by using the latest optimized version of the non-viral Sleeping Beauty (SB) transposon system "SB100X-pT4." This offers the advantage of improving CAR expression on CIK cells, while reducing the amount of DNA transposase as compared to the previously employed "SB11-pT" version. SB-modified CD33.CAR-CIK cells exhibited significant antileukemic activity in vitro and in vivo in patient-derived AML xenograft models, reducing AML development when administered as an "early treatment" and delaying AML progression in mice with established disease. Notably, by exploiting an already optimized xenograft chemotherapy model that mimics human induction therapy in mice, we demonstrated for the first time that CD33.CAR-CIK cells are also effective toward chemotherapy resistant/residual AML cells, further supporting its future clinical development and implementation within the current standard regimens., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Published
2020
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3. Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia.

Author

Arcangeli S, Rotiroti MC, Bardelli M, Simonelli L, Magnani CF, Biondi A, Biagi E, Tettamanti S, and Varani L

Subjects
Binding Sites, Cytotoxicity, Immunologic, Gene Expression, Humans, Immunomodulation, Immunotherapy, Adoptive, Interleukin-3 Receptor alpha Subunit antagonists & inhibitors, Interleukin-3 Receptor alpha Subunit metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Models, Molecular, Molecular Conformation, Protein Binding, Receptors, Antigen, T-Cell genetics, Structure-Activity Relationship, T-Lymphocytes immunology, T-Lymphocytes metabolism, Interleukin-3 Receptor alpha Subunit chemistry, Interleukin-3 Receptor alpha Subunit immunology, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute metabolism, Receptors, Antigen, T-Cell chemistry, Receptors, Antigen, T-Cell metabolism, Recombinant Fusion Proteins
Abstract

Chimeric antigen receptor (CAR)-redirected T lymphocytes are a promising immunotherapeutic approach and object of pre-clinical evaluation for the treatment of acute myeloid leukemia (AML). We developed a CAR against CD123, overexpressed on AML blasts and leukemic stem cells. However, potential recognition of low CD123-positive healthy tissues, through the on-target, off-tumor effect, limits safe clinical employment of CAR-redirected T cells. Therefore, we evaluated the effect of context-dependent variables capable of modulating CAR T cell functional profiles, such as CAR binding affinity, CAR expression, and target antigen density. Computational structural biology tools allowed for the design of rational mutations in the anti-CD123 CAR antigen binding domain that altered CAR expression and CAR binding affinity without affecting the overall CAR design. We defined both lytic and activation antigen thresholds, with early cytotoxic activity unaffected by either CAR expression or CAR affinity tuning but later effector functions impaired by low CAR expression. Moreover, the anti-CD123 CAR safety profile was confirmed by lowering CAR binding affinity, corroborating CD123 is a good therapeutic target antigen. Overall, full dissection of these variables offers suitable anti-CD123 CAR design optimization for the treatment of AML., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Published
2017
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