For many years, disappointing results have been generated by many investigations, which have utilized a variety of immunologic strategies to enhance the ability of a patient's immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient's immune system can recognize and reject his tumor if appropriate strategies are implemented. The success immunotherapy is due to the development of at least three therapeutic strategies. They include tumor-associated antigen (TAA)-specific monoclonal antibodies (mAbs), T cell checkpoint blockade, and TAA-specific chimeric antigen receptors (CARs) T cell-based immunotherapy. However, the full realization of the therapeutic potential of these approaches requires the development of strategies to counteract and overcome some limitations. They include off-target toxicity and mechanisms of cancer immune evasion, which obstacle the successful clinical application of mAbs and CAR T cell-based immunotherapies. Thus, we and others have developed the Fc gamma chimeric receptors (Fcγ-CRs)-based strategy. Like CARs, Fcγ-CRs are composed of an intracellular tail resulting from the fusion of a co-stimulatory molecule with the T cell receptor ζ chain. In contrast, the extracellular CAR single-chain variable fragment (scFv), which recognizes the targeted TAA, has been replaced with the extracellular portion of the FcγRIIIA (CD16). Fcγ-CR T cells have a few intriguing features. First, given in combination with mAbs, Fcγ-CR T cells mediate anticancer activity in vitro and in vivo by an antibody-mediated cellular cytotoxicity mechanism. Second, CD16-CR T cells can target multiple cancer types provided that TAA-specific mAbs with the appropriate specificity are available. Third, the off-target effect of CD16-CR T cells may be controlled by withdrawing the mAb administration. The goal of this manuscript was threefold. First, we review the current state-of-the-art of preclinical CD16-CR T cell technology. Second, we describe its in vitro and in vivo antitumor activity. Finally, we compare the advantages and limitations of the CD16-CR T cell technology with those of CAR T cell methodology.

Caratelli, S., Sconocchia, T., Arriga, R., Coppola, A., Lanzilli, G., Lauro, D., et al. (2017). FCγ chimeric receptor-engineered T cells: Methodology, advantages, limitations, and clinical relevance. FRONTIERS IN IMMUNOLOGY, 8(APR) [10.3389/fimmu.2017.00457].

FCγ chimeric receptor-engineered T cells: Methodology, advantages, limitations, and clinical relevance

ARRIGA, ROBERTO;LAURO, DAVIDE;VENDITTI, ADRIANO;DEL PRINCIPE, MARIA ILARIA;BUCCISANO, FRANCESCO;SCONOCCHIA, GIUSEPPE
2017

Abstract

For many years, disappointing results have been generated by many investigations, which have utilized a variety of immunologic strategies to enhance the ability of a patient's immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient's immune system can recognize and reject his tumor if appropriate strategies are implemented. The success immunotherapy is due to the development of at least three therapeutic strategies. They include tumor-associated antigen (TAA)-specific monoclonal antibodies (mAbs), T cell checkpoint blockade, and TAA-specific chimeric antigen receptors (CARs) T cell-based immunotherapy. However, the full realization of the therapeutic potential of these approaches requires the development of strategies to counteract and overcome some limitations. They include off-target toxicity and mechanisms of cancer immune evasion, which obstacle the successful clinical application of mAbs and CAR T cell-based immunotherapies. Thus, we and others have developed the Fc gamma chimeric receptors (Fcγ-CRs)-based strategy. Like CARs, Fcγ-CRs are composed of an intracellular tail resulting from the fusion of a co-stimulatory molecule with the T cell receptor ζ chain. In contrast, the extracellular CAR single-chain variable fragment (scFv), which recognizes the targeted TAA, has been replaced with the extracellular portion of the FcγRIIIA (CD16). Fcγ-CR T cells have a few intriguing features. First, given in combination with mAbs, Fcγ-CR T cells mediate anticancer activity in vitro and in vivo by an antibody-mediated cellular cytotoxicity mechanism. Second, CD16-CR T cells can target multiple cancer types provided that TAA-specific mAbs with the appropriate specificity are available. Third, the off-target effect of CD16-CR T cells may be controlled by withdrawing the mAb administration. The goal of this manuscript was threefold. First, we review the current state-of-the-art of preclinical CD16-CR T cell technology. Second, we describe its in vitro and in vivo antitumor activity. Finally, we compare the advantages and limitations of the CD16-CR T cell technology with those of CAR T cell methodology.
Pubblicato
Rilevanza internazionale
Recensione
Esperti anonimi
Settore MED/13 - Endocrinologia
Settore MED/09 - Medicina Interna
Settore MED/15 - Malattie del Sangue
Settore MED/06 - Oncologia Medica
English
Con Impact Factor ISI
Antitumor activity; CD16-CR T cells; Chimeric antigen receptor T cells; CRC; Fc gamma chimeric receptor; Hematologic malignancies; Immunotherapy; Solid tumor; Immunology and Allergy; Immunology
http://journal.frontiersin.org/article/10.3389/fimmu.2017.00457/full
Caratelli, S., Sconocchia, T., Arriga, R., Coppola, A., Lanzilli, G., Lauro, D., et al. (2017). FCγ chimeric receptor-engineered T cells: Methodology, advantages, limitations, and clinical relevance. FRONTIERS IN IMMUNOLOGY, 8(APR) [10.3389/fimmu.2017.00457].
Caratelli, S; Sconocchia, T; Arriga, R; Coppola, A; Lanzilli, G; Lauro, D; Venditti, A; DEL PRINCIPE, Mi; Buccisano, F; Maurillo, L; Ferrone, S; Sconocchia, G
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/181032
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