NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease

S Mastaglio, P Genovese, Z Magnani, E Ruggiero, E Landoni, B Camisa, G Schiroli, E Provasi, A Lombardo, A Reik, N Cieri, Martina Rocchi, Giacomo Oliveira, G Escobar, M Casucci, B Gentner, A Spinelli, A Mondino, A Bondanza, L VagoM Ponzoni, F Ciceri, MC Holmes, L Naldini, C Bonini

Research output: Contribution to journalArticle

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Abstract

Transfer of T-cell receptors (TCRs) specific for tumor-associated antigens is a promising approach for cancer immunotherapy. We developed the TCR gene editing technology that is based on the knockout of the endogenous TCR a and b genes, followed by the introduction of tumor-specific TCR genes, and that proved safer and more effective than conventional TCR gene transfer. Although successful, complete editing requires extensive cell manipulation and 4 transduction procedures. Here we propose a novel and clinically feasible TCR “single editing” (SE) approach, based on the disruption of the endogenous TCR a chain only, followed by the transfer of genes encoding for a tumor-specific TCR. We validated SE with the clinical grade HLA-A2 restricted NY-ESO-1 157-165 –specific TCR. SE allowed the rapid production of high numbers of tumor-specific T cells, with optimal TCR expression and preferential stem memory and central memory phenotype. Similarly to unedited T cells redirected by TCR gene transfer (TCR transferred [TR]), SE T cells efficiently killed NY-ESO-1 pos targets; however, although TR cells proved highly alloreactive, SE cells showed a favorable safety profile. Accordingly, when infused in NSG mice previously engrafted with myeloma, SE cells mediated tumor rejection without inducing xenogeneic graft-versus-host disease, thus resulting in significantly higher survival than that observed in mice treated with TR cells. Overall, single TCR gene editing represents a clinically feasible approach that is able to increase the safety and efficacy of cancer adoptive immunotherapy. © 2017 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)606-618
Number of pages13
JournalBlood
Volume130
Issue number5
DOIs
Publication statusPublished - 2017

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T-cells
Graft vs Host Disease
T-Cell Antigen Receptor
Multiple Myeloma
Grafts
T-Cell Receptor Genes
T-Lymphocytes
Data storage equipment
Tumors
Neoplasms
Genes
Gene transfer
HLA-A2 Antigen
Adoptive Immunotherapy
Safety
Neoplasm Antigens
Immunotherapy
Gene encoding
Technology
Phenotype

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NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. / Mastaglio, S; Genovese, P; Magnani, Z; Ruggiero, E; Landoni, E; Camisa, B; Schiroli, G; Provasi, E; Lombardo, A; Reik, A; Cieri, N; Rocchi, Martina; Oliveira, Giacomo; Escobar, G; Casucci, M; Gentner, B; Spinelli, A; Mondino, A; Bondanza, A; Vago, L; Ponzoni, M; Ciceri, F; Holmes, MC; Naldini, L; Bonini, C.

In: Blood, Vol. 130, No. 5, 2017, p. 606-618.

Research output: Contribution to journalArticle

Mastaglio, S, Genovese, P, Magnani, Z, Ruggiero, E, Landoni, E, Camisa, B, Schiroli, G, Provasi, E, Lombardo, A, Reik, A, Cieri, N, Rocchi, M, Oliveira, G, Escobar, G, Casucci, M, Gentner, B, Spinelli, A, Mondino, A, Bondanza, A, Vago, L, Ponzoni, M, Ciceri, F, Holmes, MC, Naldini, L & Bonini, C 2017, 'NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease', Blood, vol. 130, no. 5, pp. 606-618. https://doi.org/10.1182/blood-2016-08-732636
Mastaglio, S ; Genovese, P ; Magnani, Z ; Ruggiero, E ; Landoni, E ; Camisa, B ; Schiroli, G ; Provasi, E ; Lombardo, A ; Reik, A ; Cieri, N ; Rocchi, Martina ; Oliveira, Giacomo ; Escobar, G ; Casucci, M ; Gentner, B ; Spinelli, A ; Mondino, A ; Bondanza, A ; Vago, L ; Ponzoni, M ; Ciceri, F ; Holmes, MC ; Naldini, L ; Bonini, C. / NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. In: Blood. 2017 ; Vol. 130, No. 5. pp. 606-618.
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abstract = "Transfer of T-cell receptors (TCRs) specific for tumor-associated antigens is a promising approach for cancer immunotherapy. We developed the TCR gene editing technology that is based on the knockout of the endogenous TCR a and b genes, followed by the introduction of tumor-specific TCR genes, and that proved safer and more effective than conventional TCR gene transfer. Although successful, complete editing requires extensive cell manipulation and 4 transduction procedures. Here we propose a novel and clinically feasible TCR “single editing” (SE) approach, based on the disruption of the endogenous TCR a chain only, followed by the transfer of genes encoding for a tumor-specific TCR. We validated SE with the clinical grade HLA-A2 restricted NY-ESO-1 157-165 –specific TCR. SE allowed the rapid production of high numbers of tumor-specific T cells, with optimal TCR expression and preferential stem memory and central memory phenotype. Similarly to unedited T cells redirected by TCR gene transfer (TCR transferred [TR]), SE T cells efficiently killed NY-ESO-1 pos targets; however, although TR cells proved highly alloreactive, SE cells showed a favorable safety profile. Accordingly, when infused in NSG mice previously engrafted with myeloma, SE cells mediated tumor rejection without inducing xenogeneic graft-versus-host disease, thus resulting in significantly higher survival than that observed in mice treated with TR cells. Overall, single TCR gene editing represents a clinically feasible approach that is able to increase the safety and efficacy of cancer adoptive immunotherapy. {\circledC} 2017 by The American Society of Hematology.",
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T1 - NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease

AU - Mastaglio, S

AU - Genovese, P

AU - Magnani, Z

AU - Ruggiero, E

AU - Landoni, E

AU - Camisa, B

AU - Schiroli, G

AU - Provasi, E

AU - Lombardo, A

AU - Reik, A

AU - Cieri, N

AU - Rocchi, Martina

AU - Oliveira, Giacomo

AU - Escobar, G

AU - Casucci, M

AU - Gentner, B

AU - Spinelli, A

AU - Mondino, A

AU - Bondanza, A

AU - Vago, L

AU - Ponzoni, M

AU - Ciceri, F

AU - Holmes, MC

AU - Naldini, L

AU - Bonini, C

PY - 2017

Y1 - 2017

N2 - Transfer of T-cell receptors (TCRs) specific for tumor-associated antigens is a promising approach for cancer immunotherapy. We developed the TCR gene editing technology that is based on the knockout of the endogenous TCR a and b genes, followed by the introduction of tumor-specific TCR genes, and that proved safer and more effective than conventional TCR gene transfer. Although successful, complete editing requires extensive cell manipulation and 4 transduction procedures. Here we propose a novel and clinically feasible TCR “single editing” (SE) approach, based on the disruption of the endogenous TCR a chain only, followed by the transfer of genes encoding for a tumor-specific TCR. We validated SE with the clinical grade HLA-A2 restricted NY-ESO-1 157-165 –specific TCR. SE allowed the rapid production of high numbers of tumor-specific T cells, with optimal TCR expression and preferential stem memory and central memory phenotype. Similarly to unedited T cells redirected by TCR gene transfer (TCR transferred [TR]), SE T cells efficiently killed NY-ESO-1 pos targets; however, although TR cells proved highly alloreactive, SE cells showed a favorable safety profile. Accordingly, when infused in NSG mice previously engrafted with myeloma, SE cells mediated tumor rejection without inducing xenogeneic graft-versus-host disease, thus resulting in significantly higher survival than that observed in mice treated with TR cells. Overall, single TCR gene editing represents a clinically feasible approach that is able to increase the safety and efficacy of cancer adoptive immunotherapy. © 2017 by The American Society of Hematology.

AB - Transfer of T-cell receptors (TCRs) specific for tumor-associated antigens is a promising approach for cancer immunotherapy. We developed the TCR gene editing technology that is based on the knockout of the endogenous TCR a and b genes, followed by the introduction of tumor-specific TCR genes, and that proved safer and more effective than conventional TCR gene transfer. Although successful, complete editing requires extensive cell manipulation and 4 transduction procedures. Here we propose a novel and clinically feasible TCR “single editing” (SE) approach, based on the disruption of the endogenous TCR a chain only, followed by the transfer of genes encoding for a tumor-specific TCR. We validated SE with the clinical grade HLA-A2 restricted NY-ESO-1 157-165 –specific TCR. SE allowed the rapid production of high numbers of tumor-specific T cells, with optimal TCR expression and preferential stem memory and central memory phenotype. Similarly to unedited T cells redirected by TCR gene transfer (TCR transferred [TR]), SE T cells efficiently killed NY-ESO-1 pos targets; however, although TR cells proved highly alloreactive, SE cells showed a favorable safety profile. Accordingly, when infused in NSG mice previously engrafted with myeloma, SE cells mediated tumor rejection without inducing xenogeneic graft-versus-host disease, thus resulting in significantly higher survival than that observed in mice treated with TR cells. Overall, single TCR gene editing represents a clinically feasible approach that is able to increase the safety and efficacy of cancer adoptive immunotherapy. © 2017 by The American Society of Hematology.

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