Chimeric antigen receptor (CAR) T-cell therapy has been shown to be dramatically effective in the treatment of B-cell malignancies. However, there are still substantial obstacles to overcome, before similar responses can be achieved in patients with solid tumors. We evaluated both in vitro and in a preclinical murine model the efficacy of different 2nd and 3rd generation CAR constructs targeting GD2, a disial-ganglioside expressed on the surface of neuroblastoma (NB) tumor cells. In order to address potential safety concerns regarding clinical application, an inducible safety switch, namely inducible Caspase-9 (iC9), was also included in the vector constructs. Our data indicate that a 3rd generation CAR incorporating CD28.4-1BB costimulatory domains is associated with improved anti-tumor efficacy as compared with a CAR incorporating the combination of CD28.OX40 domains. We demonstrate that the choice of 4-1BB signaling results into significant amelioration of several CAR T-cell characteristics, including: 1) T-cell exhaustion, 2) basal T-cell activation, 3) in vivo tumor control and 4) T-cell persistence. The fine-tuning of T-cell culture conditions obtained using IL7 and IL15 was found to be synergic with the CAR.GD2 design in increasing the anti-tumor activity of CAR T cells. We also demonstrate that activation of the suicide gene iC9, included in our construct without significantly impairing neither CAR expression nor anti-tumor activity, leads to a prompt induction of apoptosis of GD2.CAR T cells. Altogether, these findings are instrumental in optimizing the function of CAR T-cell products to be employed in the treatment of children with NB.

Quintarelli, C., Orlando, D., Boffa, I., Guercio, M., Polito, V. A., Petretto, A., Lavarello, C., Sinibaldi, M., Weber, G., Del Bufalo, F., Giorda, E., Scarsella, M., Petrini, S., Pagliara, D., Locatelli, F., De Angelis, B., Caruana, I., Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma, <<ONCOIMMUNOLOGY>>, 2018; 7 (6): e1433518-1-e1433518-16. [doi:10.1080/2162402X.2018.1433518] [https://hdl.handle.net/10807/230034]

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma

Locatelli, Franco
Writing – Review & Editing
;
2018

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has been shown to be dramatically effective in the treatment of B-cell malignancies. However, there are still substantial obstacles to overcome, before similar responses can be achieved in patients with solid tumors. We evaluated both in vitro and in a preclinical murine model the efficacy of different 2nd and 3rd generation CAR constructs targeting GD2, a disial-ganglioside expressed on the surface of neuroblastoma (NB) tumor cells. In order to address potential safety concerns regarding clinical application, an inducible safety switch, namely inducible Caspase-9 (iC9), was also included in the vector constructs. Our data indicate that a 3rd generation CAR incorporating CD28.4-1BB costimulatory domains is associated with improved anti-tumor efficacy as compared with a CAR incorporating the combination of CD28.OX40 domains. We demonstrate that the choice of 4-1BB signaling results into significant amelioration of several CAR T-cell characteristics, including: 1) T-cell exhaustion, 2) basal T-cell activation, 3) in vivo tumor control and 4) T-cell persistence. The fine-tuning of T-cell culture conditions obtained using IL7 and IL15 was found to be synergic with the CAR.GD2 design in increasing the anti-tumor activity of CAR T cells. We also demonstrate that activation of the suicide gene iC9, included in our construct without significantly impairing neither CAR expression nor anti-tumor activity, leads to a prompt induction of apoptosis of GD2.CAR T cells. Altogether, these findings are instrumental in optimizing the function of CAR T-cell products to be employed in the treatment of children with NB.
2018
Inglese
Quintarelli, C., Orlando, D., Boffa, I., Guercio, M., Polito, V. A., Petretto, A., Lavarello, C., Sinibaldi, M., Weber, G., Del Bufalo, F., Giorda, E., Scarsella, M., Petrini, S., Pagliara, D., Locatelli, F., De Angelis, B., Caruana, I., Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma, <<ONCOIMMUNOLOGY>>, 2018; 7 (6): e1433518-1-e1433518-16. [doi:10.1080/2162402X.2018.1433518] [https://hdl.handle.net/10807/230034]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/230034
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