Despite the progress in the treatment of acute myeloid leukemia (AML) achieved in the last decades, a significant number of patients are still refractory to or relapse after standard cures. Hence, to improve cure rates of AML, it is crucial to develop novel therapeutic strategies. Immunotherapy with T cells genetically modified to express chimeric antigen receptors (CARs) represent a valid option in this sense. CARs are artificial molecules constituted by an extracellular-antigen-binding domain derived from a monoclonal antibody and an intracellular-signalling region that is immediately triggered after antigen recognition. Therefore, CARs combine the antigen binding properties of mononoclonal antibodies to T cell mediated effector functions, including the killing mechanism -that might be active against antibody resistant targets-, cytokine secretion- that might boost the anti-tumoral immune response- and capacity to efficiently home and infiltrate tumor sites. Different CARs have been generated so far, against a wide range of surface molecules expressed by many tumors and, currently, several phase I clinical trials are undergoing and the results obtained so far are very encouraging. The CARs approach can be employed to selectively target AML cells due to the overexpression of myeloid antigens, like CD33 and CD123. We recently demonstrated that expression of CD33-specific CARs in a population of ex-vivo activated T cells, called “cytokine induced killer” (CIK) cells, confers them potent in vitro anti-leukemic functions. However, since CD33 antigen is also expressed on normal haematopoietic stem/progenitors cells (HSPCs) resulting in a potential severe impairment of normal myelopoiesis, CD123 has recently been proposed as a new potential attractive molecule based on its differential expression pattern, being widely overexpressed by AML population and at the same time less expressed on HSPCs. In order to improve the safety profile against these cells we develop and test a novel CAR specific for the CD123 antigens. Here we describe the in vitro and the in vivo efficacy and the safety of this approach based on CIK cells genetically modified to express CAR molecules specific for the CD33 or CD123 antigen. The development and the optimization of the proposed strategy could be a good potential therapeutic tool in the context of minimal residual disease in high-risk transplanted AML patients. Moreover, CAR approach could be potentially used to treat patients resistant to conventional chemotherapeutic approaches or for whom high dose chemotherapy treatment could not be proposed.

(2013). Chimeric antigen receptor: a cell therapy based approach for the treatment of acute myeloid leukemia. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2013).

Chimeric antigen receptor: a cell therapy based approach for the treatment of acute myeloid leukemia

PIZZITOLA, IRENE
2013

Abstract

Despite the progress in the treatment of acute myeloid leukemia (AML) achieved in the last decades, a significant number of patients are still refractory to or relapse after standard cures. Hence, to improve cure rates of AML, it is crucial to develop novel therapeutic strategies. Immunotherapy with T cells genetically modified to express chimeric antigen receptors (CARs) represent a valid option in this sense. CARs are artificial molecules constituted by an extracellular-antigen-binding domain derived from a monoclonal antibody and an intracellular-signalling region that is immediately triggered after antigen recognition. Therefore, CARs combine the antigen binding properties of mononoclonal antibodies to T cell mediated effector functions, including the killing mechanism -that might be active against antibody resistant targets-, cytokine secretion- that might boost the anti-tumoral immune response- and capacity to efficiently home and infiltrate tumor sites. Different CARs have been generated so far, against a wide range of surface molecules expressed by many tumors and, currently, several phase I clinical trials are undergoing and the results obtained so far are very encouraging. The CARs approach can be employed to selectively target AML cells due to the overexpression of myeloid antigens, like CD33 and CD123. We recently demonstrated that expression of CD33-specific CARs in a population of ex-vivo activated T cells, called “cytokine induced killer” (CIK) cells, confers them potent in vitro anti-leukemic functions. However, since CD33 antigen is also expressed on normal haematopoietic stem/progenitors cells (HSPCs) resulting in a potential severe impairment of normal myelopoiesis, CD123 has recently been proposed as a new potential attractive molecule based on its differential expression pattern, being widely overexpressed by AML population and at the same time less expressed on HSPCs. In order to improve the safety profile against these cells we develop and test a novel CAR specific for the CD123 antigens. Here we describe the in vitro and the in vivo efficacy and the safety of this approach based on CIK cells genetically modified to express CAR molecules specific for the CD33 or CD123 antigen. The development and the optimization of the proposed strategy could be a good potential therapeutic tool in the context of minimal residual disease in high-risk transplanted AML patients. Moreover, CAR approach could be potentially used to treat patients resistant to conventional chemotherapeutic approaches or for whom high dose chemotherapy treatment could not be proposed.
BIAGI, ETTORE
BONNET, DOMINIQUE
acute Myeloid Leukemia, immunotherapy, chimeric antigen receptor
MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
English
18-gen-2013
SCUOLA DI DOTTORATO IN MEDICINA TRASLAZIONALE E MOLECOLARE (DIMET) - 72R
25
2011/2012
open
(2013). Chimeric antigen receptor: a cell therapy based approach for the treatment of acute myeloid leukemia. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2013).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/40113
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