Although dose intensification of chemotherapy has increased initial response rates in neuroblastoma (NB), this effect has not translated into durable remissions in patients with disseminated disease. Immunotherapy may be an alternative approach following cytoreductive chemotherapy providing a long-term disease control (I). We have engineered human cytotoxic T lymphocytes (CTL) to express a chimeric receptor (CR) for the specific recognition of GD2 that is expressed in NB (II). Chimeric lymphocytes (CL) have been previously introduced towards several tumors (III). Thus, we have generated a novel CR consisting of a single-chain variable domain of an anti-GD2 antibody in conjunction with a signal domain of 4-1BB molecule (CD137). Retroviral particles encoding for the flag gene only (GFP), for the whole CR and for a truncated receptor were generated. Peripheral blood cells from buffy-coat were specifically stimulated and transuced obtaining a cytotoxic population of T cells having high level of transduction (50±25%). Co-culture experiments were then performed against NB cell lines. In short (4h) co-culture experiments (T:E=1:20) by Cr51 release assay, CLs exerted a powerful and specific cytotoxicity against GD2-positive NB cells, compared with truncated controls (35±5% and 10,8±4% ; p<0,05). Moreover, in a longer co-culture assay (5 days) in vitro at higher ratio (T:E =1:5), using as read-out FACS analyses targeting GD2 expressing cells, we observed a significant decrease (from 92±3% to 19±5% ; p<0.05) of the NB cells compared with controls (from 92±3% to 76,5±4% %; p<0.05). These preliminary data in vitro suggest that CL against GD2-positive NB cells may represent a powerful new tool for T-cell therapy in patients with GD2-positive NB or other GD2-positive malignancies.

An adoptive immuno-gene therapy approach targeting neuroblastoma / Caldrer, Sara; Spano, Maria Carlotta; Grisendi, Giulia; Dominici, Massimo; Paolucci, Paolo. - In: PEDIATRIC BLOOD & CANCER. - ISSN 1545-5009. - STAMPA. - 57:(2011), pp. 783-784. ((Intervento presentato al convegno SIOP tenutosi a Auckland (NZ) nel 26 - 30 October 2011.

An adoptive immuno-gene therapy approach targeting neuroblastoma.

CALDRER, Sara;SPANO, Maria Carlotta;GRISENDI, Giulia;DOMINICI, Massimo;PAOLUCCI, Paolo
2011-01-01

Abstract

Although dose intensification of chemotherapy has increased initial response rates in neuroblastoma (NB), this effect has not translated into durable remissions in patients with disseminated disease. Immunotherapy may be an alternative approach following cytoreductive chemotherapy providing a long-term disease control (I). We have engineered human cytotoxic T lymphocytes (CTL) to express a chimeric receptor (CR) for the specific recognition of GD2 that is expressed in NB (II). Chimeric lymphocytes (CL) have been previously introduced towards several tumors (III). Thus, we have generated a novel CR consisting of a single-chain variable domain of an anti-GD2 antibody in conjunction with a signal domain of 4-1BB molecule (CD137). Retroviral particles encoding for the flag gene only (GFP), for the whole CR and for a truncated receptor were generated. Peripheral blood cells from buffy-coat were specifically stimulated and transuced obtaining a cytotoxic population of T cells having high level of transduction (50±25%). Co-culture experiments were then performed against NB cell lines. In short (4h) co-culture experiments (T:E=1:20) by Cr51 release assay, CLs exerted a powerful and specific cytotoxicity against GD2-positive NB cells, compared with truncated controls (35±5% and 10,8±4% ; p<0,05). Moreover, in a longer co-culture assay (5 days) in vitro at higher ratio (T:E =1:5), using as read-out FACS analyses targeting GD2 expressing cells, we observed a significant decrease (from 92±3% to 19±5% ; p<0.05) of the NB cells compared with controls (from 92±3% to 76,5±4% %; p<0.05). These preliminary data in vitro suggest that CL against GD2-positive NB cells may represent a powerful new tool for T-cell therapy in patients with GD2-positive NB or other GD2-positive malignancies.
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Caldrer, Sara; Spano, Maria Carlotta; Grisendi, Giulia; Dominici, Massimo; Paolucci, Paolo
An adoptive immuno-gene therapy approach targeting neuroblastoma / Caldrer, Sara; Spano, Maria Carlotta; Grisendi, Giulia; Dominici, Massimo; Paolucci, Paolo. - In: PEDIATRIC BLOOD & CANCER. - ISSN 1545-5009. - STAMPA. - 57:(2011), pp. 783-784. ((Intervento presentato al convegno SIOP tenutosi a Auckland (NZ) nel 26 - 30 October 2011.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/738744
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