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4 results on '"Giordano Attianese GMP"'

1. New advances in leukaemia immunotherapy by the use of Chimeric Artificial Antigen Receptors (CARs): state of the art and perspectives for the near future

Author

Biagi, E, Marin, V, Giordano Attianese, G, Pizzitola, I, Tettamanti, S, Cribioli, E, Biondi, A, BIAGI, ETTORE, BIONDI, ANDREA, Giordano Attianese, GMP, Biagi, E, Marin, V, Giordano Attianese, G, Pizzitola, I, Tettamanti, S, Cribioli, E, Biondi, A, BIAGI, ETTORE, BIONDI, ANDREA, and Giordano Attianese, GMP

Abstract

Leukaemia immunotherapy represents a fascinating and promising field of translational research, particularly as an integrative approach of bone marrow transplantation. Adoptive immunotherapy by the use of donor-derived expanded leukaemia-specific T cells has showed some kind of clinical response, but the major advance is nowadays represented by gene manipulation of donor immune cells, so that they acquire strict specificity towards the tumour target and potent lytic activity, followed by significant proliferation, increased survival and possibly anti-tumour memory state. This is achieved by gene insertion of Chimeric T-cell Antigen Receptors (CARs), which are artificial molecules containing antibody-derived fragments (to bind the specific target), joined with potent signalling T-Cell Receptor (TCR)-derived domains that activate the manipulated cells. This review will discuss the main applications of this approach particularly focusing on the paediatric setting, raising advantages and disadvantages and discussing relevant perspectives of use in the nearest future.

Published
2011

2. Cytokine Induced Killer cells for cell therapy of acute myeloid leukemia: improvement of their immune activity by expression of CD33-specific chimeric receptors

Author

Marin, V, Pizzitola, I, Agostoni, V, Giordano Attianese, G, Finney, H, Lawson, A, Pule, M, Rousseau, R, Biondi, A, Biagi, E, PIZZITOLA, IRENE, Giordano Attianese, GMP, BIONDI, ANDREA, BIAGI, ETTORE, Marin, V, Pizzitola, I, Agostoni, V, Giordano Attianese, G, Finney, H, Lawson, A, Pule, M, Rousseau, R, Biondi, A, Biagi, E, PIZZITOLA, IRENE, Giordano Attianese, GMP, BIONDI, ANDREA, and BIAGI, ETTORE

Abstract

Background. Cytokine induced killer cells are ex-vivo expanded cells with potent antitumoral activity. Cytokine induced killer cells infusion in acute myeloid leukemia patients relapsing after allogeneic hematopoietic stem cell transplant is well tolerated, but limited clinical responses were observed. To improve their effector functions against acute myeloid leukemia, we genetically modified cytokine induced killer cells with chimeric receptors specific for the CD33 myeloid antigen. Design and Methods. SFG-retroviral vectors coding for anti-CD33-zeta and anti-CD33-CD28-OX40-zeta chimeric receptors were used to transduce cytokine induced killer cells. Transduced cells were in vitro characterized for their ability to lyse leukemic targets (4-hour-51Chromium-release and 6-day co-cultures assays on human stromal mesenchymal cells), to proliferate (3H-thymidine-incorporation assay) and to secrete cytokines (Flow cytomix assay) after contact with acute myeloid leukemia cells. Their activity against normal CD34+ hematopoietic progenitors was evaluated by analyzing the colony forming unit capacity after co-incubation. Results. Cytokine induced killer cells were efficiently transduced with the anti-CD33 chimeric receptors, maintaining their native phenotype and functions and acquiring potent cytotoxicity (up to 80% lysis after 4-hour incubation) against different acute myeloid leukemia targets, as also confirmed in long-term killing experiments. Moreover, introduction of the anti-CD33 chimeric receptors was accompanied by a prominent CD33-specific proliferative activity, with a release of high levels of immunostimulatory cytokines. The presence of CD28-OX40 in chimeric receptor endodomain was associated with a significant amelioration of cytokine induced killer cells anti-leukemic activity. Importantly, even though anti-CD33 chimeric receptors-transduced cytokine induced killer cells showed toxicity against normal hematopoietic CD34+ progenitors, a residual clonogenic activ

Published
2010

3. In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor

Author

Maurilio Ponzoni, Valentina Agostoni, Virna Marin, Sarah Tettamanti, Irene Pizzitola, Paolo Ghia, Ettore Biagi, Matteo Parma, Greta Maria Paola Giordano Attianese, Valentina Hoyos, Gianpietro Dotti, Barbara Savoldo, Andrea Biondi, Maria Teresa Sabrina Bertilaccio, Giordano Attianese, G, Marin, V, Hoyos, V, Savoldo, B, Pizzitola, I, Tettamanti, S, Agostoni, V, Parma, M, Ponzoni, M, Bertilaccio, M, Ghia, P, Biondi, A, Dotti, G, Biagi, E, Giordano Attianese, Gmp, Ponzoni, Maurilio, Bertilaccio, Mt, Ghia, PAOLO PROSPERO, and Biagi, E.

Subjects
Cytotoxicity, Immunologic, Cell therapy, CLL, chimeric TCR, CD23, Recombinant Fusion Proteins, T-Lymphocytes, Immunology, Gene Expression, Biology, Lymphocyte Activation, Immunotherapy, Adoptive, Biochemistry, Mice, Interleukin 21, stomatognathic system, Antigen, immune system diseases, Cell Line, Tumor, hemic and lymphatic diseases, Animals, Humans, Cytotoxic T cell, IL-2 receptor, Antigen-presenting cell, Mice, Knockout, B-Lymphocytes, Receptors, IgE, ZAP70, hemic and immune systems, Gene Therapy, Cell Biology, Hematology, Natural killer T cell, Leukemia, Lymphocytic, Chronic, B-Cell, Xenograft Model Antitumor Assays, Molecular biology, Coculture Techniques, DNA-Binding Proteins, Cytokines, Interleukin-2, CD5
Abstract

Chronic lymphocytic leukemia (CLL) is characterized by an accumulation of mature CD19(+)CD5(+)CD20(dim) B lymphocytes that typically express the B-cell activation marker CD23. In the present study, we cloned and expressed in T lymphocytes a novel chimeric antigen receptor (CAR) targeting the CD23 antigen (CD23. CAR). CD23.CAR(+) T cells showed specific cytotoxic activity against CD23(+) tumor cell lines (average lysis 42%) and primary CD23(+) CLL cells (average lysis 58%). This effect was obtained without significant toxicity against normal B lymphocytes, in contrast to CARs targeting CD19 or CD20 antigens, which are also expressed physiologically by normal B lymphocytes. Moreover, CLL-derived CD23.CAR(+) T cells released inflammatory cytokines (1445-fold more TNF-beta, 20-fold more TNF-alpha, and 4-fold more IFN-gamma). IL-2 was also produced (average release 2681 pg/mL) and sustained the antigen-dependent proliferation of CD23.CAR(+) T cells. Redirected T cells were also effective in vivo in a CLL Rag2(-/-)gamma(-/-)(c) xenograft mouse model. Compared with mice treated with control T cells, the infusion of CD23. CAR(+) T cells resulted in a significant delay in the growth of the MEC-1 CLL cell line. These data suggest that CD23. CAR(+) T cells represent a selective immunotherapy for the elimination of CD23(+) leukemic cells in patients with CLL. (Blood. 2011; 117(18): 4736-4745) Chronic lymphocytic leukemia (CLL) is characterized by an accumulation of mature CD19(+)CD5(+)CD20(dim) B lymphocytes that typically express the B-cell activation marker CD23. In the present study, we cloned and expressed in T lymphocytes a novel chimeric antigen receptor (CAR) targeting the CD23 antigen (CD23. CAR). CD23.CAR(+) T cells showed specific cytotoxic activity against CD23(+) tumor cell lines (average lysis 42%) and primary CD23(+) CLL cells (average lysis 58%). This effect was obtained without significant toxicity against normal B lymphocytes, in contrast to CARs targeting CD19 or CD20 antigens, which are also expressed physiologically by normal B lymphocytes. Moreover, CLL-derived CD23.CAR(+) T cells released inflammatory cytokines (1445-fold more TNF-beta, 20-fold more TNF-alpha, and 4-fold more IFN-gamma). IL-2 was also produced (average release 2681 pg/mL) and sustained the antigen-dependent proliferation of CD23.CAR(+) T cells. Redirected T cells were also effective in vivo in a CLL Rag2(-/-)gamma(-/-)(c) xenograft mouse model. Compared with mice treated with control T cells, the infusion of CD23. CAR(+) T cells resulted in a significant delay in the growth of the MEC-1 CLL cell line. These data suggest that CD23. CAR(+) T cells represent a selective immunotherapy for the elimination of CD23(+) leukemic cells in patients with CLL. (Blood. 2011; 117(18): 4736-4745)

Published
2011

4. Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes

Author

Martin Pule, Concetta Quintarelli, Gianpietro Dotti, Helen E. Heslop, Greta Maria Paola Giordano Attianese, Barbara Savoldo, Aaron E. Foster, Cliona M. Rooney, Juan F. Vera, Malcolm K. Brenner, Quintarelli, Concetta, Vera, Jf, Savoldo, B, Giordano Attianese, Gmp, Pule, M, Foster, Ae, Heslop, He, Rooney, Cm, Brenner, Mk, and Dotti, G.

Subjects
Interleukin 2, Adoptive cell transfer, Herpesvirus 4, Human, Cell Survival, medicine.medical_treatment, Immunology, Blotting, Western, Genetic Vectors, Plenary Paper, Mice, SCID, Biology, Lymphocyte Activation, Biochemistry, Immunotherapy, Adoptive, Immunophenotyping, Mice, Transduction, Genetic, medicine, Cytotoxic T cell, Animals, Humans, Transgenes, Interleukin-15, Tumor microenvironment, Lymphokine, Genes, Transgenic, Suicide, Cell Biology, Hematology, Suicide gene, Adoptive Transfer, Cytokine, Interleukin 15, Cytokines, Interleukin-2, medicine.drug, T-Lymphocytes, Cytotoxic
Abstract

The antitumor effect of adoptively transferred tumor-specific cytotoxic T lymphocytes (CTLs) is impaired by the limited capacity of these cells to expand within the tumor microenvironment. Administration of interleukin 2 (IL-2) has been used to overcome this limitation, but the systemic toxicity and the expansion of unwanted cells, including regulatory T cells, limit the clinical value of this strategy. To discover whether transgenic expression of lymphokines by the CTLs themselves might overcome these limitations, we evaluated the effects of transgenic expression of IL-2 and IL-15 in our model of Epstein Barr Virus–specific CTLs (EBV-CTLs). We found that transgenic expression of IL-2 or IL-15 increased the expansion of EBV-CTLs both in vitro and in vivo in a severe combined immunodeficiency disease (SCID) mouse model and enhanced antitumor activity. Although the proliferation of these cytokine genes transduced CTLs remained strictly antigen dependent, clinical application of this approach likely requires the inclusion of a suicide gene to deal with the potential development of T-cell mutants with autonomous growth. We found that the incorporation of an inducible caspase-9 suicide gene allowed efficient elimination of transgenic CTLs after exposure to a chemical inducer of dimerization, thereby increasing the safety and feasibility of the approach.

Published
2007

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